Piperidine derivatives having anxiolytic effect

ABSTRACT

Piperidine compounds having the general formula (I), ##STR1## wherein R 1  is a group having general formula (II), ##STR2## wherein X is CHR 10 , O, S, SO, SO 2  or NR 10 , Z 1  is CH 2 , O, or S; Z 2  and Z 3  are independently (CH 2 ) n , n being 0 or 1, O or S or Z 1  and Z 2  may together represent a group --CH═CH--; or when Z 3  is (CH 2 ) n  wherein n is 0, Z 1  and Z 2  may together represent a 3-membered divalent group; show potent sigma receptor activity. Furthermore they show effect in animal models indicative of anxiolytic properties. Accordingly they are useful as medicines for the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cerebrovascular diseases, senile demential of the Alzheimer type or Parkinson&#39;s disease.

This is a continuation of international application Ser. No.PCT/DK92/00183, filed Jun. 12, 1992.

The present invention relates to a class of piperidine compounds havinganxiolytic effect and potently binding to the sigma receptors andtherefore being useful in the treatment of psychic and neurologicdisorders.

Various related compounds are known from the prior art.

So, U.S. Pat. Nos. 3,686,186 and 3,745,165 disclosespiro[phthalan-1,4'-piperidine] and spiro[isochroman-3,4'-piperidine]compounds optionally having a benzyl substituent at the piperidineN-atom. The phthalan compounds are said to be useful as antidepressantsas indicated by their ability to reverse reserpine hypothermia, whereasthe isochromane compounds are stated to be useful ashypotriglyceridemics.

German Offenlegungsschrift No. 2,458,176 and the corresponding U.S. Pat.No. 3,985,889 generically describe inter alia1,3-dihydrospiro[isobenzofuran-1,4'-piperidine] or1,3-dihydrospiro[isobenzofuran-1,3'-pyrrolidine] compounds substitutedat the ring N-atom with lower alkyl, cycloalkyl or phenyl(C₂₋₄)alkyl andoptionally having an oxo group attached to the furan ring. The compoundsare alleged to be useful as tranquilizers as demonstrated by theirability to display effects on behaviour and reflex depression and onmuscle relaxation, and they are claimed also to be useful in thetreatment of pain as demonstrated in the 2-phenyl-1,4-quinone inducedwrithing assay in mice. However, only pharmacological data for one suchcompound without an oxo substituent in the furan ring, i.e. the compound1,3-dihydro-1'-methyl-spiro[isobenzofuran-1,4'-piperidine], arepresented, and only four such compounds having a substituent differentfrom methyl on the piperidine N-atom are specifically disclosed, i.e.1'-cyclopropylmethyl-, 1'-[3-(4-fluoro-benzoyl)propyl]-,1'-[4,4-bis(4-fluorophenyl)butyl]- and1'-acetyl-1,3-dihydrospiro[iso-benzofuran-1,4'-piperidine]. Noindication of effect on sigma-receptors is given.

Japanese patent publication JP Kokai 55 143,980 generically describesinter alia a very broad class of spiro[chromane-piperidine] compoundswhich are optionally substituted at the piperidine N-atom with an alkyl,cycloalkyl, allyl, aryl, aralkyl, or arylcycloalkyl group ahd optionallysubstituted in the chromane ring with an oxo group. However, withrespect to such spirochromane compounds having no oxo substituent in thechromane ring only compounds having a methyl, phenyl or benzyl group atthe piperidine N-atom are specifically disclosed. These compounds areclaimed to possess antiallergic activity and no suggestion of activityin the central nervous system is given.

European patent publication No EP 0 414 289 A1 generically describes aclass of 1,2,3,4-tetrahydro-spiro[naphthalene-1,4'-piperidine] and1,4-dihydro-spiro[naphthalene-1,4'-piperidine] derivatives substitutedat the piperidine N-atom with a "hydrocarbon" and alleged to haveselective sigma receptor antagonistic activity. The term "hydrocarbon"as defined in said patent covers all possible straight chained, cyclic,heterocyclic etc. groups; however, only compounds having benzyl,phenethyl, cycloalkylmethyl, furyl- or thienylmethyl or lower alkyl oralkenyl as the "hydrocarbon" substituent at the piperidine nitrogen atombeing specifically disclosed. The compounds are stated to displacetritiated di-tolyl guanidine (DTG) from sigma sites with potenciesbetter than 200 nM. As a particularly preferred compound is mentioned1'-benzyl-1,2,3,4-tetrahydro-spiro[naphthalene-1,4'-piperidine].European patent publication No EP 0 445 974 A2 generically describes thecorresponding spiro[indane-1,4'-piperidine] andspiro[benzocycloheptene-5,4'-piperidine] derivatives. Again thecompounds are only stated to displace tritiated di-tolyl guanidine (DTG)from sigma sites with potencies better than 200 nM

EP Application No. EP-A2-0 431 943 relates to a further extremely broadclass of spiropiperidine compounds substituted at the piperidine N-atom.Said compounds are alleged to be useful as antiarrhythmics and forimpaired cardiac pump function.

Said application exemplifies several compounds, the majority of whichcontain an oxo and/or a sulfonylamino substituent in the spiro cyclicring system. Of the remainder compounds, the main part has another polarsubstituent, such as nitro, amino, a fused imidazo group etc. attachedto the spiro nucleus and/or they have some polar substituents, such assulfonylamino, nitro, amino, etc. in the substituent on the piperidineN-atom. Furthermore some of the compounds have heteroaryl alkylsubstituents on the piperidine N-atom, whereas only a very few of thosecompounds exemplifies do not have such substituents, i.e. a couple of6-methoxy-spiro[2H-1-benzopyran-2,4'-piperidines] having aphenylsubstituent on the piperidine N-atom and a fewspiro[3H-1-benzopyran-3,4'-piperidine]'s having a benzyl, phenethyl,hexyl or heptyl substituent on the piperidine N-atom. No suggestion orindication of effect of the compounds on the sigma receptors is given.

U.S. Pat. No. 4,420,485 discloses1'-[3-(6-fluoro-1,2-benzoisoxazol-3-yl)propyl]-spiro[benzofuran-2(H),4'-piperidines]optionally having one or two substituents in the benzofuran ring. Thecompounds are claimed to be useful as antihypertensives. No mention orsuggestion of effects in the treatment of psychic or neurologicaldisorders is given.

German Offenlegungsschrift No 28 27 874 corresponding to U.S. Pat. No.4,251,538 generically discloses a class of3-[4-(4-phenyl-piperidin-1-yl)-butyl]- or3-[4-(4-phenyl-tetrahydropyridyl-1-yl)-butyl]indole derivativesoptionally substituted in the indole, piperidinyl or tetrahydropyridyland/or phenyl groups. The compounds are said to show dopamine agonisteffects and serotonin reuptake inhibiting effects in the central nervoussystem, and accordingly to be useful in the treatment of Parkinson'sdisease and depression. However, no documentation for such effects isgiven in the specification, no pharmacological data at all being given,and certainly no indication or suggestion of effect on the sigmareceptor is given.

Furthermore, the majority of the compounds listed in the specification,of which obviously only a few have actually been prepared, aretetrahydropyridyl compounds and/or they have an oxo substituent in thebutyl chain. Only a few piperidyl compounds without an oxo substituentin the butyl chain are mentioned, i.e.3-[4-(4-phenyl-1-piperidyl)-butyl]-indole and the 1-methyl-, 1-phenyl-and 2-methyl- derivatives thereof as well as derivatives thereofsubstituted with halogen, methyl or trifluoromethyl in the 4-phenylsubstituent on the piperidyl group thereof. With respect to physicaldata only melting point for one such compounds is given.

International Patent Application No WO 91/09594 published on Jul. 11,1991 relates i.a. to sigma receptor ligands being 4-phenyl-piperidinecompounds and having an optionally substituted "heteroaryl"-alkyl,-alkenyl, -alkynyl, -alkoxy or -alkoxy-alkyl substituent on thepiperidine N-atom. The term "heteroaryl"-alkyl is defined by mention ofa very broad class of such substituents. However only four N-substituted4-phenyl-piperidine compounds are specifically disclosed which are all1-(phenyl-lower alkyl)-4-phenyl-piperidines and only four compoundshaving a "heteroaryl"-alkyl substituent are specifically mentioned,which are all piperazine (and not piperidine) compounds. The compoundsare stated to be antipsychotics.

From studies of the biology and function of sigma receptors, evidencehas been presented that sigma receptor ligands may be useful in thetreatment of psychosis and movement disorders, such as dystonia andtardive dyskinesia, and motor disturbances associated with Huntington'schorea or Tourette's syndrome and in is Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355). The known sigmareceptor ligand rimcazole clinically shows effects in the treatment ofpsychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry 1989, 1, 7)and a group of sigma receptor ligands have been described to showantihallucinogenic activity in animal models (International PatentPublication No WO 9103243).

Furthermore, sigma receptor ligands have been reported to be involved inmodulation of NMDA receptor mediated events in the brain and to act asanti-ischemic agents in in vivo tests (Rao, T. S. et al, MolecularPharmacology, 1990, 37, 978). In addition to ischemia they may also beuseful in the treatment of other such NMDA receptor mediated events,e.g. epilepsy and convulsion.

Also, some sigma receptor ligands have been found to show anti-amnesiceffects in an animal model (Early et al., Brain Research 1991, 546,281-286). Sigma ligands have been shown to influence centralacetylcholine levels in animal models (Matsuno et al, Brain Research1992, 575, 315-319; Junien et al, Eur. J. Pharm. 1991, 200, 343-345) andmay, therefore, have potential in the treatment of senile dementia ofthe Alzheimer type.

Finally, some guanidine derivatives having sigma receptor activity havebeen disclosed to be useful as anxiolytics (International PatentPublication No. WO 9014067).

Accordingly, agents potently acting on the sigma receptors in thecentral nervous system are believed to be of potential use in thetherapy of such conditions.

It has now been found that a certain class of piperidine compounds bindat sigma receptors with potencies which generally are 2-3 orders ofmagnitude higher than the potency limit indicated in European patentpublication EP 0 414 289 A1. Furthermore the compounds of said classhave been found to show anxiolytic effects in animal models.

Said class of compounds consists of compounds having the general FormulaI ##STR3## wherein R¹ is

a) a group -D-B-A-R

wherein B is an up to 19 membered spacer group selected from alkylene,alkenylene and alkynylene which may be branched or straight chain andoptionally substituted with hydroxy, which again may be esterified withan aliphatic carboxylic acid having from two to twentyfour carbon atoms,inclusive,

A is a bond or a divalent group selected from O, S, SO, SO₂, and##STR4## W being O or S and the dotted line designating an optionalbond; R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl,cycloalkylalkyl, cycloalkenylalkyl, phenylalkyl, diphenylalkyl, anyalkylgroup optionally being substituted with one or two hydroxy groups,which again may be optionally esterified with an aliphatic carboxylicadd having from two to twentyfour carbon atoms inclusive, and any phenylgroup being optionally substituted with one or more substituents in thephenyl ring; and

D is CR⁸ R⁹ where R⁸ and R⁹ are independently selected from thesubstituents defined below for R⁴ -R⁷, or a cycloalkylene group; or

b) a group having the general Formula II: ##STR5## wherein X is CHR¹⁰,O, S, SO, SO₂ or NR¹⁰, R¹⁰ being hydrogen, lower alkyl or alkenyl,cycloalkyl or cycloalkylalkyl, cycloalkenyl or cycloalkenylalkyl, acyl,aminoalkyl, mono- or dialkylaminoalkyl, sulfonyl or arylalkyl or phenyloptionally substituted with one or more substituents independentlyselected from the following: halogen, lower alkyl, lower alkoxy,hydroxy, trifluoromethyl, and cyano, or R¹⁰ is a hetero aromatic group,preferably 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl,2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;

one or two of the dotted lines may be a bond;

when the dotted line emanating from Y indicates a bond, Y is N or CH; or

when said dotted line indicates no bond, Y is CH₂, NH, C═O or C═S;

R^(a) -R^(d) are independently selected from hydrogen, halogen, loweralkyl, lower alkoxy, hydroxy, lower alkylthio, lower alkylsulphonyl,lower alkyl- or dialkylamino, cyano, trifluoromethyl, ortrifluoromethylthio;

U is CH₂, O or S; or

when, one of the dotted lines emanating from U indicates a bond, U isCH;

the bond between U and Q¹ or Q², respectively, may also be a triple bondand in such case U is "C";

Q¹ is selected from a bond, alkylene or alkenylene and Q² is alkylenehaving at least two C-atoms, alkenylene or a group Q² 'D wherein Q² ' isas defined for Q² and D is as defined above, Q¹ and Q² having togetherfrom 2 to 20 carbon atoms and being optionally substituted with one ormore hydroxy groups, any such hydroxy group being optionally esterifiedwith an aliphatic carboxylic acid having from two to twentyfour carbonatoms inclusive; and

R² and R³ are independently hydrogen, lower alkyl or they may be linkedtogether thereby forming an ethylene or propylene bridge;

R⁴ to R⁷ are independently selected from hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, lower alkylthio, lower alkyl- or dialkylamino,cyano, trifluoromethyl, or trifluoromethylthio; and

i) Z¹ and Z² are linked together in which case: Z¹ is CH₂, O or S;

Z² and Z³ are independently (CH₂)_(n), n being 0 or 1, O or S, with theproviso that

Z¹ may not be S or O when Z² is S or O, and that Z² and Z³ may not bothbe

(CH₂)_(n) wherein n is 0:

or Z¹ and Z² may together represent a group --CH═CH--;

or when Z³ is (CH₂)_(n) wherein n is 0, Z¹ and Z² may together representa 3-membered divalent group, optionally containing one unsaturated bond,and optionally containing one O- or S-heteroatom; or

ii) when R¹ is a group as defined in b) Z¹ and Z² may also be unlinked,in which case: Z¹ is a group as defined for R⁴ -R⁷, Z² is hydrogen andZ³ is (CH₂)_(n) wherein n is 0;

with the proviso that when Z¹ -Z³ are as defined in i) wherein Z³ is(CH₂)_(n) where n is 0, and Z¹ and Z² together represent a 2- or3-membered divalent hydrocarbon group, optionally containing oneunsaturated bond, and R¹ is a group defined in a) then D-B-A-R may notbe phenyl-C₁₋₃ -alkyl, lower alkyl or lower alkenyl; and acid additionsalts or prodrugs thereof.

Accordingly the present invention provides the use of piperidinecompounds having the above defined general Formula I or acid additionsalts or prodrugs thereof for the manufacture of a pharmaceuticalpreparation for the treatment of anxiety, psychosis, epilepsy,convulsion, movement disorders, motor disturbances, amnesia,cerebrovascular diseases, senile dementia of the Alzheimer type orParkinson's disease.

Some of the compounds of the general Formula I may exist as opticalisomers thereof; and such optical isomers am also embraced by theinvention.

The term alkyl is intended to mean a C₁ -C₂₀ straight chain or branchedalkyl group and similarly alkenyl means a C₂ -C₂₀ straight chain orbranched alkenyl group having one or more unsaturated bonds in thechain. The term cycloalkyl designates a carbocyclic ring having 3-8carbon atoms inclusive or a bicyclic or tricyclic carbocycle, such asadamantyl.

The terms lower alkyl, lower alkoxy, lower alkylthio, etc. designatesuch branched or unbranched groups having from one to six carbon atomsinclusive. Exemplary of such groups are methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl,methoxy, ethoxy,1-propoxy, 2-propoxy, methylthio, ethylthio,1-propylthio, 2-propylthio, methylsulphonyl, ethylsulphonyl, or thelike.

Halogen means fluoro, chloro, bromo or iodo.

The term "sulfonyl" is used in the meaning alkyl or aryl substitutedsulfonyl, and similarly "acyl" is used in the meaning alkyl- orarylcarbonyl

The term "one or two of the dotted lines may be a bond" is intended tomean that each of the dotted lines may or may not represent a bond, i.e.that the ring and the side chain respectively may or may not have adouble bond in the positions of the dotted lines in Formula II, providedthat only two at a time indicate a bond and that adjacent dotted linesdo not both indicate a bond.

The optional substituents in the phenyl groups in the definition af Rmay independently be selected from halogen, lower alkyl, lower alkoxy,hydroxy, lower alkylthio, lower alkylsulphonyl, lower alkyl- ordialkylamino, cyano, trifluoromethyl, or trifluoromethlthio. Each phenylgroup may carry one or more substituents.

The acid addition salts of the invention are pharmaceutically acceptablesalts of the compounds of Formula I formed with non-toxic acids.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-amino-benzoic, glutamic, benzene sulfonic and theophylline aceticacids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids.

The movement disorders and motor disturbances which may be treated bythe preparation according to the invention are e.g. dystonia and tardivedyskinesia and motor disturbances associated with Huntington's chorea orTourette's syndrome. Dystonia may be acute or tardive and may be causedby neuroleptics or have another reason.

Cerebrovascular diseases are such disorders caused by cerebralinfarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoidhemorrhage, cerebral thrombosis, cerebral embolism, or the like, e.g.ischemia, hypoxia, anoxia.

The compounds of the invention have been found to displace tritiateddi-tolyl guanidine (DTG) from sigma sites in vitro with potencies betterthan about 40 nM, and the great majority better than 1 nM, i.e. they arebinding at the sigma receptors much more potently than sigma receptorligands such as e.g. BMY 14802 and rimcazole. Furthermore, most of thepresent compounds have proven to be very selective ligands on the sigmareceptors. For example as compared to the α₁ adrenoceptors and dopamineD₂ receptors, the main part of the present compounds have been found toshow ratios of binding affinities (IC₅₀ alpha/sigma and dopamine/sigma,respectively) of 30-10000. Furthermore, the compounds have proven toshow very potent anxiolytic effects in an animal behaviour test inextremely low doses i.e. with EC₅₀ values in the ng-μg/kg range.

When Z¹ and Z² are linked together, preferably at least one of Z¹, Z²and Z³ designates O or S, and more preferably Z³ is (CH₂)_(n) wherein nis 0, and Z² is "O" or "S" and Z¹ is CH₂ or Z¹ and Z² together representCH₂ --O--CH₂. Other preferred groups are those wherein Z¹ is CH₂, Z² isO and Z³ is CH₂ ; or Z³ is O and Z¹ -Z² is CH═CH; or Z¹ is O, Z³ is Oand Z² is (CH₂)_(n) where n=0,

Particularly preferred compounds are:

1'-(3-Adamantyloxy-1-propyl)spiro[3 H-2-benzopyran-3,4'-piperidine];

1'-[4-(1-Benzyl-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine];

1'-(3-(3-Phenylimidazolidin-2-on-1-yl)-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine];

1,4-Dihydro-1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]spiro[3H-2-benzopyran-3,4'-piperidine];

1'-(4-(1-p-Toluenesulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[5-Fluoro-1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];

6-Fluoro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-Methylphenyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine];

1-(4-Fluorophenyl)-3-[4-(4-(4-fluorophenyl)-1-piperidyl)-1-butyl]indole;

1'-[4-(1-(2-Thiazolyl)-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[3-(5-Fluorobenzofuran-3-yl)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-(5-Fluorobenzofuran-3-yl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine];

1'-[4-[1-(4-Fluorophenyl)-5-trifluoromethylindazol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];

4-Fluorophenyl-3-[4-(4-(4-fluorophenyl)-1-piperidinyl)-1-butyl]-5-trifluoromethylindazol;

1'-(4-(1,2-Benzisoxazol-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];and

1'-[3-(Benzo[b]thiophen-3-ylthio)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine].

Some of the compounds used in accordance with the invention are novel,and accordingly in another aspect the present invention relates to novelpiperidine derivatives having the general Formula I as defined abovewith the proviso that if R¹ is a group of the Formula II as definedabove under b), Z¹, Z², and Z³ are as defined above under ii), X is NH,Y is CH and the dotted line emanating from Y indicates a bond, then --Q¹--U--Q² -- may not be alkyl having less than 5 carbon atoms;

if R¹ is a group of the Formula II as defined above wherein Z³ is O, Z¹is CH₂, Z² is (CH₂)_(n), n being 0, X is O, Y is N, the dotted lineemanating from Y indicates a bond, and --Q¹ --U--Q² -- indicates--(CH₂)₃, then R^(c) may not be fluoro;

if Z³ is O, Z² and Z¹ are both CH₂ and D-B-A-R is optionally substitutedphenethyl, then R⁶ may not be methoxy; and

if Z¹ is O, and Z² and Z³ are both CH₂, then D-B-A-R may not bephenethyl, or optionally hydroxy substituted hexyl or heptyl.

The present invention also provides a pharmaceutical compositioncomprising at least one novel piperidine compound according to theinvention as defined above or a pharmaceutically acceptable acidaddition salt thereof or prodrug therefore in combination with one ormore pharmaceutically acceptable carriers or diluents.

The pharmaceutical compositions of this invention or those which aremanufactured in accordance with this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions methods well known in the artmay be used, and any pharmaceutically acceptable carriers, diluents,excipients, or other additive usually used in in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compound in an amount of about 0.01 to 50mg.

The total daily dose usually ranges of about 0.05-100 mg, and mostpreferably about 0.1 to 20 mg of the active compound of the invention.

The compounds of Formula I may be prepared by:

a) reducing the amide carbonyl of a compound of Formula III ##STR6##wherein R² -R⁷ and Z¹ -Z³ are as previously defined and R¹¹ is such agroup that CH₂ --R¹¹ is a group comprised by the definition of R¹ ;

b) alkylating a compound of Formula IV ##STR7## wherein R² -R⁷ and Z¹-Z³ are as previously defined, with an alkylating reagent of the formulaR¹ --V wherein R¹ is as previously defined and V is a suitable leavinggroup such as halogen, mesylate or tosylate;

c) reductive alkylation of amines of Formula IV with aldehydes of theformula R¹¹ --CHO or carboxylic acids of the formula R¹¹ --COOH orketones of the formula R¹² --CO--R¹³ wherein R² -R⁷, R¹¹, and Z¹ -Z³ areas previously defined and R¹² and R¹³ are such groups that R¹² --CH--R¹³is a group comprised by the definition of R¹ ;

d) reducing the C═Y¹ double bond in a compound of Formula V ##STR8##wherein R^(a) -R^(d), X, U, Q¹, Q², R² -R⁷, and Z¹ -Z³ are as previouslydefined and Y¹ is CH or N;

e) oxidizing a compound of Formula VI to an oxo compound of Formula VII:##STR9## wherein R^(a) -R^(d), X, U, Q¹, Q², R² -R⁷, and Z¹ -Z³ are aspreviously defined;

f) alkylating a compound of Formula VIII for obtaining a compound ofgeneral Formula I wherein X═NR¹⁰ ', R¹⁰ ' being lower alkyl, alkenyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl or cycloalkenylalkyl,##STR10## wherein R^(a) -R^(d), Y, U, Q¹, Q², R² -R⁷, and Z¹ -Z³ are aspreviously defined, with an alkylating reagent of the formula R¹⁰ '--V¹,wherein R¹⁰ ' is as previously defined and V¹ is a suitable leavinggroup, e.g. halogen, mesylate, or tosylate; or acylating a compound ofthe Formula VIII with an acylating reagent having the formula R¹⁰"--CO--Hal, wherein Hal is halogen and R¹⁰ " is a group which togetherwith CH₂ form the group R¹⁰ ', and subsequently reducing the acylatedcompound of Formula VIII;

g) arylating a compound of Formula VIII for obtaining a compound ofgeneral Formula I wherein X═NR¹⁰ '", R¹⁰ '" being optionally substitutedphenyl or heteroaryl, with an arylating agent of the formula Ar--V¹wherein Ar is optionally substituted phenyl or heteroaryl and V¹ is aspreviously defined;

h) for obtaining a compound of general Formula I wherein X═N--CO--R¹⁰ 'or N--CO--Ar, wherein R¹⁰ ' and Ar are as previously defined, acylatinga compound of Formula VIII with an acylating agent of the formula R¹⁰'--CO--Hal or Ar--CO--Hal, wherein Hal is as previously defined;

i) for obtaining a compound of general Formula I wherein X═N--SO₂ --R¹⁰' or N--SO₂ --Ar, wherein R¹⁰ ' and Ar are as previously defined,sulfonylating a compound of Formula VIII with a sulfonylating agent ofthe formula R¹⁰ '--SO₂ --Hal or Ar--SO₂ --Hal, wherein Hal is aspreviously defined;

j) reductive alkylation of compounds of Formula VIII with carbonylcompounds of formula R¹⁴ --CO--R¹⁵ wherein R¹⁴ and R¹⁵ are such groupsthat R¹⁴ --CH--R¹⁵ is a group R¹⁰ as previously defined;

k) making a ring closure reaction of the hydrazone IX to the indazolederivative X ##STR11## wherein R^(a) -R^(d), U, Q¹, Q², R² -R⁷, R¹⁰, andZ¹ -Z³ are as previously defined and Hal is halogen;

I) reducing the quarternized pyridine derivative of Formula Xl ##STR12##in which R¹ -R⁷, Z¹ and V¹ are as previously defined; whereupon thecompound of Formula I is isolated as the free base or a pharmaceuticallyacceptable acid addition salt thereof.

The reduction according to method a) may preferably be carried out in aninert organic solvent such as diethyl ether or tetrahydrofuran in thepresence of lithium aluminium hydride at reflux temperature.

The amides of Formula III are conveniently prepared by treatingpiperidine derivatives of Formula IV with suitable carboxylic acidchlorides of formula R¹¹ --COCl in the presence of base (potassiumcarbonate or triethylamine). When R¹¹ --CH₂ designates a group offormula -D-B-A-R the corresponding carboxylic acid chlorides of formulaR¹¹ --COCl are either commercially available or prepared according tostandard procedures.

When R¹¹ --CH₂ designates a group of Formula II the correspondingcarboxylic acid chlorides of Formula XII, ##STR13## wherein R^(a)-R^(d), X, Y, U, and Q¹ are as previously defined and Q² ' is such agroup that Q² '--CH₂ is a group Q² as previously defined, are preparedfrom the corresponding carboxylic acids by known methods.

The piperidine derivatives of Formula IV where Z¹ and Z² are linkedtogether, are prepared as follows:

Spiro[isobenzofuran-1(3H),4'-piperidine] according to the methoddescribed by Marxer et al, J. Org. Chem. 1975, 40, 1427.

2,3-Dihydro-spiro[1H-indene-1,4'-piperidine] and3,4-dihydro-spiro[naphthalene-1(2H)-4'-piperidine] according to themethod described in French Patent. No. 1,335,831.

1'-Methyl-spiro[benzo[c]thiophene-1(3H),4'-piperidine] according to themethod described by Parham et al, J. Org. Chem. 1976, 41, 2628. Thecorresponding demethylated derivative was obtained by treatment withethyl chloroformate followed by alkaline hydrolysis of the intermediaryethyl carbamate.

1'-Phenylmethyl-spiro[1H-2-benzopyran-4(3H),4'-piperidine] according tothe method described by Yamamoto et al, J. Med. Chem., 1981, 24, 194.The corresponding debenzylated derivative is obtained by hydrogenationin the presence of a palladium catalyst.

3,4-Dihydro-1'-phenylmethyl-spiro[2H-1-benzopyran-2,4'-piperidine]according to the method described by Yamamoto et al, Chem. Pharm. Bull.1981, 29, 3494. The corresponding debenzylated derivative is obtained bytreatment with ethyl chloro- formate followed by alkaline hydrolysis ofthe intermediary ethyl carbamate.

1'-Phenylmethyl-spiro[2H-1-benzopyran-2,4'-piperidine] is obtainedaccording to the method described by Yamamoto et al, Chem. Pharm. Bull.1981, 29, 3494. The corresponding debenzylated derivative is obtained byhydrogenation in the presence of a palladium catalyst.

1'-Phenylmethyl-spiro[3H-2-benzopyran-3,4'-piperidine]-1(4H)-oneaccording to the method described by Yamamoto et al, J. Med. Chem. 1981,24, 194. Reduction with lithium aluminium hydride followed by treatmentwith phosphoric acid according to the procedure described by Marxer etal, J. Org. Chem. 1975, 40, 1427 yields1,4-dihydro-1'-phenylmethyl-spiro[3H-2-benzopyran-3,4'-piperidine] whichis debenzylated by hydrogenation in the presence of a palladiumcatalyst.

1'-Benzylspiro[4H-1-benzopyran-4,4'-piperidine] is obtained by a methodanalogously to the method described in EP 0 414 289 A1 for the synthesisof 1'-benzyl-1,4-dihydrospiro[naphtalene-1,4'-piperidine]. Hydrogenationin the presence of a palladium catalyst gave2,3-dihydrospiro[4H-1-benzopyran-4,4'-piperidine].

Spiro[1,3-benzodioxole-2,4'-piperidine] is obtained by refluxing1-ethoxycarbonyl-4-piperidinone and catechol in toluene solution in thepresence of p-toluenesulfonic acid with continuous removal of waterfollowed by removal of the benzyl group by hydrogenation in the presenceof a palladium catalyst.

The substituents R² -R⁷ are introduced by applying suitably substitutedstarting compounds to methods analogously to the above mentioned.

The piperidine derivatives of Formula IV where Z¹ and Z² are not linkedare prepared by known methods, see e.g. U.S. Pat. No. 2,891,066;McElvain et al J. Amer. Chem. Soc. 1950, 72, 3134; Bally et al Chem.Ber. 1887, 20, 2590.

Alkylation of a compound of Formula IV according to method b) isconveniently performed in an inert organic solvent such as a suitablyboiling alcohol or ketone, preferably in the presence of a base(potassium carbonate or triethyl amine) at reflux temperature.

The alkylating reagents of formula R¹ --V where R¹ designates -D-B-A-Rwherein A is O, S, or a bond and D, B, and R are as previously defined,are prepared by standard literature methods. The correspondingsulfoxides and sulfones are obtained by oxidation of the sulfidesaccording to methods well known in the art.

Such alkylating agent in which A represents a group ##STR14## wherein Wis O

or S are prepared by the method disclosed in DE-OS No 2035370.

The preparations of alkylating reagents of formula R¹ --V where R¹designates a group having the general Formula II are illustrated byexamples in the following reaction schemes. In the formulas of thereaction schemes R^(a) -R^(d), V and Ar are as previously defined, and Edesignates a 1-piperidyl group of general Formula IV. Indenes of FormulaII are conveniently prepared according to Scheme 1, in which R^(a)-R^(d) and V are as previously defined. ##STR15##

Method 1 is a conventional Reformatsky condensation performed withactivated zinc. Method 2 consists of a lithium aluminium hydridereduction performed in an inert organic solvent such as diethyl ether ortetrahydrofuran at reflux temperature,

The elimination in Method 3 is preferably performed in a suitablealcohol, e.g. methanol, in the presence of a strong mineral acid, e.g.concentrated hydrochloric acid. Preferably, Method 4 is treatment withmethanesulfonyl chloride in the presence of triethyl amine indichloromethane, thus giving the corresponding methanesulfonate, but mayalternatively be conversion of the hydroxy group to a halogen by meansof a suitable reagent, e.g. thionyl choride.

Indanes of Formula II are prepared according to Scheme 2, in which R^(a)-R^(d) and V are as previously defined. ##STR16##

Method 1a is analogous to Method 1 with the modification thatelimination of water is performed directly on the crude product by meansof concentrated hydrochloric acid. The mixture of isomers obtained isreduced according to Method 2. One of the isomers obtained is isolatedwhile the remaining mixture is hydrogenated in a conventional Parrapparatus (Method 5) in the presence of a suitable noble metal catalyst,e.g. palladium or platinum.

Indoles of Formula II are most conveniently prepared either from indolealkanoic acid, exemplified by indole butanoic acid as described in Eur.Pat. Appl. No. 376607, or according to Scheme 3, in which R^(a) -R^(d),Ar and V are as previously defined. ##STR17##

The starting indoxyl ester is prepared by the method described in U.S.Pat. No. 4,710,500 and references therein. The alkylation in Method 5 isperformed in an inert, suitably boiling, organic solvent, e.g. analcohol or a ketone, preferably in the is presence of a base (potassiumcarbonate or triethyl amine). The decarboxylation in Method 6 ispreferably performed thermally, after hydrolysis of the diester to thediacid, in a suitable inert solvent, e.g. quinoline, dimethyl formamide,or N-methyl-2-pyrrolidinone (NMP) in the presence of copper.

Indol-3-yloxypropyl derivatives can also be obtained by heating amixture of 3-acetoxyindoles and 1,3-propylene glycol in the presence ofsulfuric acid, thereby obtaining 3-(indol-3-yloxy)-1-propanolderivatives which are converted to the corresponding methanesulfonatesor halides by Method 4.

Benzofuranes and 2,3-dihydrobenzofuranes of Formula II are preparedaccording to Schemes 4 and 5, in which R^(a) -R^(d) and E are aspreviously defined. ##STR18##

Method 7 is a conventional conversion to the methyl ester by treatingthe carboxylic acid with thionyl chloride followed by addition ofmethanol to the intermediate carboxylic acid chloride. The2,3-dihydrobenzofuranes are obtained by reduction with magnesium (Method8) at this stage, while the benzofuranes are obtained by skipping thisstep. Method 9 consists of conversion of the alcohol group to thecorresponding chloride by means of thionyl chloride followed bytreatment with dimethyl malonate in a suitable solvent, e.g. NMP, in thepresence of base, preferably potassium tert-butoxide. Method 11 issimilar to Method 6 except the decarboxylation is performed withoutaddition of copper. ##STR19##

Method 12 consists of a conventional conversion of the carboxylic acidto the amide via the carboxylic acid chloride. Prolongation of the sidechain is accomplished by conversion of the hydroxy group to the chlorideby treatment with preferably thionyl chloride in dichloromethane in thepresence of a few drops of dimethyl formamide (Method 13) followed bytreatment with a cyanide salt, e.g. potassium cyanide, in a suitableaprotic dipolar solvent, preferably dimethyl sulfoxide, at 100°-200° C.(Method 14). Hydrolysis of the cyano group is accomplished with mineralacid at elevated temperature (Method 15).

Benzo[b]thiophenes and 2,3-dihydrobenzo[b]thiophenes of Formula II areprepared by methods analogous to the methods described in Schemes 4 and5. Benzo[b]thiophen-3-ylmethyloxyethyl derivatives are prepared frommethyl benzo[b]thiophene-3-carboxylate by reduction to the methanolderivative with lithium aluminium hydride followed by alkylation withethyl bromoacetate and subsequent reduction tobenzo[b]thiophen-3-ylmethyloxyethanol derivatives which are converted tothe target compounds via Method 4. Benzofuran-3-ylmethyloxyethylderivatives are prepared analogously.

Benzo[b]thiophene-S,S-dioxide derivatives are obtained by oxidation ofthe corresponding benzo[b]thiophene derivatives according to standardliterature methods. 2,3-Dihydroindoles of Formula II are prepared bymethods analogous to method d). Indolones of Formula II are prepared bymethods analogous to method e). Indazoles of Formula II are prepared bymethods analogous to method j).

Reductive alkylation of amines of Formula IV according to method c) isperformed by standard literature procedures. The aldehydes, carboxylicacids, and ketones of formulas R¹¹ --CHO, R¹¹ --COOH, and R¹² --CO--R¹³,respectively, are either commercially available or are preparedaccording according to standard procedures or according to methodsanalogous to the methods described in Schemes 1-5.

Reduction of the C═Y¹ double bond according to method d) is convenientlyperformed by catalytic hydrogenation in an alcohol with a platinumcatalyst or by hydrogenation with diborane or a diborane precursor suchas trimethyl amine or dimethyl sulfide complex in tetrahydrofuran ordioxane from 0° C. to reflux temperature, followed by acid catalyzedhydrolysis of the intermediate borane derivative.

Alternatively, the double bond can be reduced by sodium borohydride inmethanol in the presence of trifluoroacetic acid (see e.g. Berger. et alJ. Med. Chem. 1977, 20, 600).

Oxidation of a compound of Formula VI according to method d) isperformed according to Szabo-Pustay et al., Synthesis, 1979, 276.

Alkylation, acylation or sulfonylation of compounds of Formula VIIIaccording to methods f), h) and i), respectively, are performed in aninert solvent such as a suitably boiling alcohol or ketone, preferablyin the presence of a base (potassium carbonate or triethyl amine). Thealkylating reagents R¹⁰ '--V¹, the acylating reagents R¹⁰ "--CO--V¹, R¹⁰'--CO--V¹, and Ar--CO--V¹, and the sulfonylation reagents R¹⁰ '--SO₂--V¹, and Ar--SO₂ --V¹ respectively, are commercially available or areprepared by standard procedures.

Arylation of a compound of Formula VIII according to method g) is mostconveniently performed by applying the well known Ullmann reaction. Thearylating reagents Ar--V¹ are commercially available.

Reductive alkylation of compounds of Formula VIII according to method j)are performed by standard literature methods.

The ring closure of compounds of Formula IX according to method k) ismost conveniently performed by heating a compound of Formula IX in asuitable inert organic solvent such as dimethyl formamide in thepresence of a base, preferably potassium tert-butoxide.

Hydrazones of Formula IX are prepared according to Scheme 6, in whichR^(a) -R^(d), R¹⁰ and Hal are as previously defined. ##STR20##

Method 16 is an addition of the Grignard reagent of 4-chloro-1-butanolto o-halobenzonitriles under standard conditions for Grignard reactions.Conversion to the hydrazone (Method 17) is accomplished by reflux inethanol in the presence of a hydrazine. Alternatively, the hydroxyderivative resulting from Method 16 may be converted to the amine viathe corresponding mesylate analogous to Method 4 and a) beforeconversion of the keto group.

The reduction according to method I) is most conveniently performed bycatalytic hydrogenation in an alcohol with a platinum catalyst.Compounds of Formulas V, VI, and VIII are prepared by methods a), b),j), k), or l). Compounds of Formula XI are prepared by treating acompound of formula R¹ --V¹ with a 4-aryl-pyridine in a suitably boilingalcohol.

In the following the invention is further illustrated by examples which,however, may not be construed as limiting:

EXAMPLE 1

1'-Butylspiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 1a.

A mixture of spiro[isobenzofuran-1(3H),4'-piperidine] (2 g), n-butylbromide (4 g), potassium carbonate (5 g), and potassium iodide (0.2 g)in 100 ml of 4-methyl-2-pentanone was refluxed for 16 h. After coolingthe reaction mixture was washed with 100 ml of water and concentrated invacuo. The title compound crystallized as the oxalate salt from acetoneby addition of oxalic acid. Recrystallized from an ethanol/ethermixture. Yield: 1.2 g, mp: 171°-73° C.

In a similar manner was also prepared:1'-Pentylspiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 1b, mp:170°-72° C.

EXAMPLE 2

1'-(4-Phenyl-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine], fumarate,2a

To an ice cooled solution of 4-phenyl-1-butanol (20 g) and triethylamine (15 g) in 200 ml of dichloromethane, a solution of methanesulfonylchloride (12 ml) in 50 ml of dichloromethane was added dropwise. Afterstirring for 1 h at 10° C. the reaction mixture was washed with water.Extraction of the water phase with dichloromethane, drying of thecombined organic phases over MgSO₄ followed by removal of the volatilecomponents in vacuo, gave 29 g of a slightly yellow oil,4-phenyl-1-butyl methanesulfonate, which was sufficiently pure for usein the next step. A mixture of spiro[isobenzofuran-1(3H),4'-piperidine](2 g), 4-phenyl-1-butyl methanesulfonate (6 g) and potassium carbonate(14 g) in 75 ml of 4-methyl-2-pentanone was refluxed for 20 h. Aftercooling the reaction mixture was filtered and concentrated in vacuo. Theremaining viscous oil was applied to a silica gel column(eluent:ether/methanol/triethyl amine=93:5:2) giving a colorless oilwhich crystallized as the fumarate salt, 2a, from acetone by addition offumaric acid. Yield: 0.7 g, mp: 197°-99° C.

In a similar manner were also prepared:

1'-(4-Cyclohexyl-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 2b, mp: 139°-42° C.

2,3-Dihydro-1'-(4-phenyl-1-butyl)spiro[1H-indene-1,4'-piperidine],fumarate, 2c, mp: 207°-11° C.

1'-(4-Phenyl-1-butyl)spiro[benzo[c]thiophene-1(3H),4'-piperidine],maleate, 2d, mp: 176°-77° C.

3,4-Dihydro-1'-(4-phenyl-1-butyl)spiro[naphtalene-1(2H),4'-piperidine]fumarate,2e, mp: 191°-93° C.

1'-(4-Phenyl-1-butyl)spiro[1H-2-benzopyran-4(3H),4'-piperidine],maleate, 2f, mp: 169°-70° C.

1,4-Dihydro-1'-(4-phenyl-1-butyl)spiro[3H-2-benzopyran-3,4'-piperidine],maleate, 2g, mp: 152°-53° C.

3,4-Dihydro-1'-(4-phenyl-1-butyl)spiro[2H-1-benzopyran-2,4'-piperidine],oxalate, 2h, mp: 155°-57° C.

1'-(4-Phenyl-1-butyl)spiro[2H-1-benzopyran-2,4'-piperidine], fumarate,2i, mp: 184°-85° C.

1'-(3-Cyclohexyloxy-1'-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],fumarate, 2j, mp: 154°-55° C.

1'-(3-Phenoxy-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine], 2k, mp:143°-44° C.

1'-(3-Phenoxy-1-propyl)spiro[3H-2-benzopyran-3,4'-piperidine], maleate,2l, mp: 171°-73° C.

1'-(3-Adamantyloxy-1-propyl)spiro[3H-2-benzopyran-3,4'-piperidine],maleate, 2m, mp: 221°-24° C.

1'-(3-Methylthio-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 2n, mp: 126°-27° C.

1'-(3-Cyclohexylthio-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 2o, mp: 170°-74° C.

1'-(3-Phenylthio-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate,2p, 152°-55° C.

1'-(3-Methylsulfonyl-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],2q, mp: 163°-64° C.

1'-(3-Cyclohexylsulfonyl-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],2r, mp: 118°-20° C.

1'-(3-Phenylsulfonyl-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],2s, mp: 197°-202° C.

8'-(4-Phenyl-1-butyl)spiro[isobenzofuran-1(3H),3'-8-azabicyclo[3,2,1]octane],maleate, 2t, mp: 180°-81° C.

1'-[4-(3-Indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine], 2u,mp: 150°-55° C.

1'-[4-(3-Indolyl)-1-butyl]-spiro[1H-2-benzopyran-4(3H),4'-piperidine],oxalate, 2v, mp: 222°-25° C.

1'-[5-(3-Indolyl)-1-pentyl]-spiro[1H-2-benzopyran-4(3H),4'-piperidine],oxalate, 2x, mp: 145°-46° C.

1'-[6-(3-Indolyl)-1-hexyl]-spiro[1H-2-benzopyran-4(3H),4'-piperidine],oxalate, 2y, mp: 117°-18° C.

1'-[4-(5,6-Dichloro-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],2z, mp: 122°-23° C.

1'-[4-(5-Fluoro-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],2aa, mp: 185°-87° C.

1'-[4-(1-Methyl-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],2bb, mp: 101°-2° C.

3-[4-(4-Phenyl-1-piperidyl)-1-butyl]indole, 2cc, mp: 131°-32° C.

3-[4-(4-(3,4-Dichlorophenyl)-1-piperidyl)-1-butyl]indole, 2dd, mp:118°-19° C.

5,6-Dichloro-3-[4-(4-(4-fluorophenyl)-1-piperidyl)-1-butyl]-indole, 2ee,mp: 120°-21° C.

3-[6-(4-(4-Fluorophenyl)-1-piperidinyl)-1-hexyl]indole, 2ff, mp: 90°-91°C.

3-[4-(4-(2-Methoxyphenyl)-1-piperidinyl)-1-butyl]indol, oxalate, 2gg,mp: 183°-88° C.

1'-[4-(1-Benzyl-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],2hh, mp: 166°-68° C.

3-[4-(4-(4-Fluorophenyl)-1-piperidyl)-1-butyl]indol-2-one, 2ii, mp:108°-10° C.

6-Fluoro-1'-(4-(3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],2jj, mp: 189°-91° C.

EXAMPLE 3

1'-(4-(3-Cyclohexylimidazolidin-2-on-1-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],hydrochloride, 3a.

A mixture of 1-cyclohexyl-3-(4-chloro-1-butyl)-2-imidazolidinon (2.0 g,prepared according to the method described in Ger. Offen. 2035370),spiro[isobenzofuran-1(3H),4'-piperidine] (1.5 g), potassium carbonate(4.4 g), and potassium iodide (0.1 g) in 60 ml of methyl isobutyl ketonewas refluxed for 17 h. After cooling to room temperature the mixture wasfiltered and the solvent removed in vacuo. The remaining oil waspurified by column chromatography (silica gel, eluent:ethylacetate/heptane/triethyl amine=9:1:1). The title compound crystallizedas the hydrochloride from an acetone/ether mixture by addition of enetheral solution of HCl. Yield: 1.9 g, mp: 203°-7° C.

In a similar manner were also prepared:

1'-(2-(3-Phenylimidazolidin-2-on-1-yl)-1-ethyl)spiro[isobenzofuran-1(3H),4'-piperidine],hydrochloride, 3b, mp: 151°-54° C.

1'-(3-(3-Phenylimidazolidin-2-on-1-yl)-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],hydrochloride, 3c, mp: 232°-50° C.

1'-(2-(3-Cyclohexylimidazolidin-2-on-1-yl)-1-ethyl)spiro[isobenzofuran-1(3H),4'-piperidine],hydrochloride, 3d, mp: 160°-61° C.

EXAMPLE 4

1'-Propyl-spiro[isobenzofuran-1(3H),4'-piperidine], maleate, 4a.

To a mixture of spiro[isobenzofuran-1(3H),4'-piperidine] (3 g),potassium carbonate (5 g), and 100 ml of water in 100 ml of toluene,propionyl chloride (3 g) was added dropwise. After stirring for 3 h atroom temperature the toluene phase was separated, washed with water andconcentrated in vacuo.

The remaining oil was dissolved in 100 ml of tetrahydrofuran and lithiumaluminium hydride (1 g) was added. After 3 h of reflux the reactionmixture was cooled and, successively, water (2 ml), 9N NaOH (1 ml), andwater (5 ml) was added. The mixture was filtered and concentrated invacuo and the title compound crystallized as the maleate salt, 4a, fromethyl acetate by addition of maleic acid. Recrystallized from anacetone/ether mixture. Yield: 0.7 g, mp: 107°-9° C.

In a similar manner were also prepared:

1'-(5-Methyl-1-hexyl)-spiro[isobenzofuran-1(3H),4'-piperidine], oxalate,4b, mp: 162°-64° C.

1'-(2-Phenyl-1-ethyl)-spiro[isobenzofuran-1(3H),4'-piperidine], maleate,4c, mp: 161°-63° C.

1'-(3-Phenyl-1-propyl)-spiro[isobenzofuran-1(3H),4'-piperidine],maleate, 4d, mp: 142°-44° C.

1'-(5-Phenyl-1-pentyl)-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 4e, mp: 115°-17° C.

1'-(6-Phenyl-1-hexyl)-spiro[isobenzofuran-1(3H)4'-piperidine], oxalate,4f, mp: 156°-57° C.

1'-Octadecanyl-spiro[isobenzofuran-1(3H),4'-piperidine], oxalate, 4g,mp: 208°-10° C.

EXAMPLE 5

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],5a.

A mixture of 2u (3 g), 1-fluoro-4-iodobenzene (5 g), copper powder (0.5g), and potassium carbonate (2 g) in 50 ml of NMP was kept at 160°-170°C. for 5 h. After filtration, water was added followed by extractionwith ether. Removal of solvent in vacuo gave a red oil which was appliedto a silica get column (eluent:ethyl acetate). The title compound, 5a,crystallized as the oxalate salt from acetone by addition of oxalicacid. Yield: 1.3 g, mp: 169°-70° C.

In a similar manner were also prepared:

1,4-Dihydro-1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]spiro[3H-2-benzopyran-3,4'-piperidine],maleate, 5b, mp: 142°-43° C.

1'-[4-[1-(3-Thienyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],5c, mp: 182°-83° C.

1'-[4-[1-(2-Thienyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],5d, mp: 198°-202° C.

1'-[4-[1-(3-Furanyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],5e, mp: 141°-42° C.

1-(4-Fluorophenyl)-3-[4-(4-phenyl-1-piperidyl)-1-butyl]indole, oxalate,5f, mp: 171°-73° C.

1'-[4-[1-(4-Pyridyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 5g, mp: 127°-29° C.

EXAMPLE 6

1'-(4-(1-Methanesulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 6a.

A solution of NaOH (20 g) in water (20 ml) was cooled to 10° C. and asolution of 4-(3-indolyl)-1-butanol (4 g) in methylene chloride (60 ml)was added together with tetrabutylammonium Hydrogensulfate (0.8 g).Methanesulfonyl chloride (2.5 ml) in methylene chloride (25 ml) wasadded dropwise at 15° C. followed by stirring for 20 min. at roomtemperature. The phases were separated and the organic phase washed withwater. Drying over magnesium sulfate and removal of solvent in vacuogave an oil which was purified by column chromatography (silica gel,eluent:ether/methylene chloride/heptane=1:1:1) giving 1.8 g of a heavyoil, 4-(1-methanesulfonyl-3-indolyl)-1-butyl methanesulfonate which wasconverted to the title compound by the method described in EXAMPLE 2.The oxalate salt crystallized from acetone by addition of oxalic acid.Yield: 1.0 g, mp: 83°-85° C.

In a similar manner were also prepared:

1'-(4-(1-p-Toluenesulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 6b, mp: 201°-4° C.6-Fluoro-1'-(4-(1-(2-thienyl)sulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 6c, mp: 184°-86° C.

EXAMPLE 7

1'-(4-(1-Acetyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 7.

A solution of acetyl chloride (0.8 ml) in methylene chloride (10 ml) wasadded dropwise at 15° C. to a mixture of 2u (1.8 g), sodium hydroxide (1g), and tetrabutylammonium hydrogensulfate (0.2 g) in methylene chloride(40 ml). After stirring for 1 h at room temperature water was added, theorganic phase separated and dried over magnesium sulfate. Filtration andremoval of solvent in vacuo gave a viscous oil which was purified bycolumn chromatography (silica gel, eluent:heptane/ethyl acetate/triethylamine=60:40:4). The title compound crystallized as the oxalate salt fromacetone by addition of oxalic acid. Yield: 0.45 g, mp: 139°-40° C.

EXAMPLE 8

1'-[3-[1-(4-Fluorophenyl)-3-indolyloxy]-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 8a.

A mixture of 3-acetyloxy-1-phenylindole (24 g), 1,3-dihydroxypropane(240 ml), and conc. sulfuric acid (10 ml) was heated to 80° C. for 2 h.Water was added followed by extraction with ether. The ether phase wasdried over magnesium sulfate followed by removal of solvent in vacuogiving 3-(1-phenyl-3-indolyloxy)-1-propanol, sufficiently pure for usein the next step. The title compound was obtained by the methoddescribed in EXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine]and crystallized as the oxalate salt from acetone by addition of oxalicacid. Yield: 2 g, mp: 151°-54° C.

In a similar manner were also prepared:

1'-[3-[6-Chloro-1-(4-fluorophenyl)-3-indolyloxy]-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 8b, mp: 180°-81° C.

1'-[3'-[5-Chloro-1-(4-fluorophenyl)-3-indolyloxy]-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 8c, mp: 115°-18° C.

5-Chloro-1-(4-fluorophenyl)-3-[3-(4-(4-methylphenyl)-1-piperidinyl)-1-propyloxy]indol,8d, mp: 111°-12° C.

EXAMPLE 9

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine],maleate, 9a.

A tetrahydrofuran solution (500 ml) of methyl 4-(3-indolyl)-butyrate(103 g) was added dropwise to a suspension of lithium aluminium hydride(25 g) in tetrahydrofuran (1000 ml) at 40° C. followed by stirring for 1h at room temperature. Usual work-up gave 4-(3-indolyl)-1-butanol (96 g)as an oil. Arylation with 1-fluoro-4-iodobenzene according to the methoddescribed in EXAMPLE 5 yielded4-[1-[4-fluorophenyl)-3-indolyl]-1-butanol which was converted to thetitle compound 9a by the method described in EXAMPLE 2 using spiro[1H-2-benzopyran-4(3H),4'-piperidine]. The maleate salt crystallized fromacetone by addition of maleic acid. Yield: 1.5 g, mp: 189°-90° C.

In a similar manner were also prepared:

1'-[4-[5-Fluoro-1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 9b, mp: 164°-65° C.

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]spiro[benzo[c]thiophene-1(3H),4'-piperidine],maleate, 9c, mp: 179°-80° C.

8'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butylspiro[isobenzofuran-1(3H),3'-8-azabicyclo[3,2,1]octane],maleate, 9d, mp: 161°-62° C.

6-Fluoro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],hydrochloride, 9e, mp: 227°-31° C.

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]-6-isopropylspiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 9f, mp: 129°-44° C.

7-Fluoro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 9g, mp: 186°-89° C.

1'-[4-[1-(4-Fluorophenyl)-3-indolyl]-1-butyl]-5-methylspiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 9h, mp: 154°-56° C.

1'-[4-[1-(4-Methylphenyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine],fumarate, 9i, mp: 186°-88° C.

1'-[4-[5-Fluoro-1-(3-thienyl)-3-indolyl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],fumarate, 9j, mp: 184°-86° C.

1'-[4-[1-(3-Pyridinyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine],fumarate, 9k, mp: 185°-87° C.

1-(4-Fluorophenyl)-3-[4-(4-(4-fluorophenyl)-1-piperidyl)-1-butyl]indole,oxalate, 9l, mp: 190°-91° C.

1-(4-Fluorophenyl)-3-[4-(4-(4-methylphenyl)-1-piperidyl)-1-butyl]indole,maleate, 9m, mp: 130°-32° C.

1-(4-Fluorophenyl)-3-[4-(4-(4-isopropylphenyl)-1-piperidyl)-1-butyl]indole,maleate, 9n, mp: 160°-62° C.

1-(4-Fluorophenyl)-3-[4-(4-(4-dimethylaminophenyl)-1-piperidyl)-1-butyl]indole,fumarate, 9o, mp: 180°-82° C.

1-Phenyl-3-[4-(4-(4-fluorophenyl)-1-piperidyl)-1-butyl]indole, oxalate,9p, mp: 174°-76° C.

1'-[4-(1-(2-Thiazolyl)-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],fumarate, 9q, mp: 165°-67° C.

6-Trifluoromethyl-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],fumarate, 9r, mp: 100°-105° C.

4-Fluoro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 9s, mp: 160°-63° C.

1-(4-Fluorophenyl)-3-[4-(4-(3-trifluoromethylphenyl)-1-piperidyl)-1-butyl]indole,maleate, 9t, mp: 112'-13° C.

2,3-Dihydro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1butyl]spiro[4H-1-benzopyran-4,4'-piperidine],oxalate, 9u, mp: 187°-92° C.

6-Fluoro-1'-[4-[5-fluoro-1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(H),4'-piperidine],oxalate, 9v, mp: 144°-46° C.

EXAMPLE 10

1'-(4'-(Benzo[b]thiophen-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],maleate, 10a.

A solution of methyl benzo[b]thiophen-3-ylacetate (69 g) in drytetrahydrofuran (100 ml) was added dropwise to a suspension of lithiumaluminium hydride (10 g) in dry tetrahydrofuran (500 ml) at roomtemperature followed by reflux for 1 h. Hydrolysis with water,filtration and removal of solvent gave an oil which was applied to asilica gel column (eluent:methylene chloride) giving 34.5 g ofbenzo[b]thiophen-3-ylethanol as an oil. The product was dissolved in 200ml of methylene chloride, thionyl chloride (20 ml) was added followed byreflux for 5 h. Removal of solvent and excess thionyl chloride in vacuogave 3-(2-chloro-1-ethyl)-benzo[b]thiophene as an oil (45 g). Thechloride was converted to 4-benzo[b]thiophen-3-yl-1-butanol viatreatment with dimethyl malonate followed by hydrolysis, decarboxylationand reduction according to the method described in EXAMPLE 11. The titlecompound 10a was prepared from 4-benzo[b]thiophen-3-yl-1-butanol andspiro[isobenzofuran-1(3H),4'-piperidine] by the method described inEXAMPLE 2. Yield: 2.2 g, mp: 144°-45° C.

In a similar manner were also prepared:

1,4-Dihydro-1'-(4-(benzo[b]thiophen-3-yl)-1-butyl)spiro[3H-2-benzopyran-3,4'-piperidine],maleate, 10b, mp: 172°-73° C.

1'-(4-(5-Methylbenzo[b]thiophen-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],maleate, 10c, mp: 164°-65° C.

EXAMPLE 11

2,3-Dihydro-5-fluoro-3-[3-(4-(4-fluorophenyl)-1-piperidinyl)-1-propyl]benzofuran,11a.

To a suspension of 5-fluorobenzofuran-3-carboxylic acid (118 g) in 800ml of dichloromethane, thionyl chloride (200 ml) and dimethyl formamide(1 ml) were added. After reflux for 3 h the reaction mixture wasconcentrated in vacuo, and the remaining oil dissolved in 800 ml ofdichloromethane. Methanol (1.5 l) was slowly added and the mixturestirred for 1 h. Removal of solvents in vacuo left methyl5-fluorobenzofuran-3-carboxylate (125 g) as an oil.

The oil was dissolved in methanol (1.8 l) and magnesium turnings (7 g)was added. After the reaction had started additional magnesium (80 g)was added portionswise during 1.5 h keeping the reaction temperature at30°-40° C. The reaction mixture was stirred for 1 h followed by additionof aq. ammonium chloride. Extraction with ether, drying the ether phaseover sodium sulfate followed by removal of the solvent in vacuo, left aviscous oil, methyl 2,3-dihydro-5-fluorobenzofuran-3-carboxylate (120g). The oil was dissolved in 500 ml of dry ether and added dropwise to asuspension of lithium aluminium hydride (32 g) in 600 ml of dry ether.The mixture was refluxed for 3 h followed by hydrolysis with water.Filtration and removal of solvent in vacuo gave2,3-dihydro-5-fluoro-3-hydroxymethyl-benzofuran (95 g) which wasconverted to 155 g of 2,3-dihydro-5-fluorobenzofuran-3-ylmethylmethanesulfonate by the method described in EXAMPLE 2. Dimethyl malonate(262 g) was dissolved in NMP (2 l) and potassium tert-butoxide (202 g)was added portionwise keeping the temperature at 15°-20° C. The mixturewas heated to 60° C. and a solution of2,3-dihydro-5-fluorobenzofuran-3-ylmethyl methanesulfonate (155 g) inNMP (150 ml) was added dropwise. The mixture was stirred for 4 h at70°-75° C. followed by addition of cold water. Extraction with ether,drying the ether phase over magnesium sulfate, followed by removal ofsolvent in vacuo gave dimethyl2-(2,3-dihydro-5-fluorobenzofuran-3-ylmethyl)malonate (160 g) as an oil,which was sufficiently pure for the further synthesis. The oil wasdissolved in 2 l of ethanol and a mixture of 120 g of solid potassiumhydroxide and 200 ml of water was added followed by reflux for 2 h. Thereaction mixture was concentrated in vacuo, water was added followed byextraction with ether. The water phase was acidified with concentratedhydrochloric acid and extracted with ethyl acetate. Drying of theorganic phase over magnesium sulfate and removal of solvent in vacuogave a viscous oil which was dissolved in NMP (1 l) and kept at 150° C.for 2 h. Addition of water and extraction with ether gave, after dryingover magnesium sulfate and removal of solvent in vacuo, 77 g of3-(2,3-dihydro-5-fluorobenzofuran-3-yl)-propionic acid. Reduction withlithium aluminium hydride by the method described above yielded 51 g of3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propanol which was convertedto 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate bythe method described in EXAMPLE 2. The title compound, 11a, was preparedfrom 3-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-1-propyl methanesulfonate(4.2 g) and 4-(4-fluorophenyl)piperidine (5.5 g) by the method describedin EXAMPLE 2. Yield: 1.8 g, mp: 83°-85° C.

In a similar manner was also prepared:

1'-[3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],11b, mp: 62°-63° C.

EXAMPLE 12

1'-[4-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 12.

3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared asdescribed in EXAMPLE 11, (51 g) was dissolved in 300 ml ofdichloromethane and 0.5 ml of dimethyl formamide was added. During 20min 50 ml of thionyl chloride was added dropwise followed by stirringfor 3 h. Ice cold water was added, the organic phase separated, driedover magnesium sulfate and concentrated in vacuo giving 46 g of3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil. Sodiumcyanide (12 g) was suspended in dimethyl sulfoxide (180 ml) and heatedto 80° C. A solution of3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran (42 g) in 40 ml ofdimethyl sulfoxide was added dropwise followed by heating to 140° C. for15 min. After cooling ether and water were added, the ether phaseseparated, washed with water and dried over magnesium sulfate. Removalof solvent in vacuo left a viscous oil which was applied to a silica gelcolumn giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyronitrile asan oil (20 g). The cyanide was dissolved in 100 ml of glacial aceticacid followed by addition of concentrated hydrochloric acid (200 ml).After reflux for 5 h, water was added followed by extraction with ethylacetate. Drying of the organic phase over magnesium sulfate and removalof solvent in vacuo gave 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyricacid (20 g). The acid (8 g) was dissolved in 50 ml of dichloromethaneand 0.5 ml of dimethyl formamide was added. Thionyl chloride (20 ml) wasadded followed by reflux for 1.5 h. The reaction mixture wasconcentrated twice with heptane in vacuo giving4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-butyric acid chloride (7 g) asan oil. A solution of spiro[isobenzofuran-1(3H),4'-piperidine] (2 g) andtriethyl amine (3 ml) in dichloromethane (50 ml) was cooled to 5° C. anda solution of 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)-butyric acidchloride (3 g) in dichloromethane (25 ml) was added dropwise. Afterstirring for 1 h at room temperature the reaction mixture was washedwith salt water and dried over magnesium sulfate. Removal of the solventin vacuo gave 4.4 g of a viscous oil which was dissolved in 25 ml of drytetrahydrofuran and added dropwise to a suspension of lithium aluminiumhydride (2.6 g) in 60 ml of dry tetrahydrofuran. The reaction mixturewas heated to reflux for 2 h and hydrolyzed with water. Filtration andremoval of solvent in vacuo gave a viscous oil which was applied to asilica gel column (eluent:heptane/ethyl acetate/triethyl amine=70:25:5)giving 2.9 g of the title compound, 12, which crystallized as theoxalate salt from acetone by addition of oxalic acid. Yield: 2.2 g, mp:102°-3° C.

EXAMPLE 13

1'-[4-(2,3-Dihydro-3-indolyl)-1-butyl]spiro[1,3-benzodioxole-2,4'-piperidine],oxalate, 13a.

To a solution of 25b (4 g) and BH₃ --NMe₃ (10 g) in 100 ml of dioxane,conc. hydrochloric acid (12 ml) was added. After stirring for 0.5 h themixture was refluxed for 2 h. The mixture was cooled to room temperatureand 6N hydrochloric acid (40 ml) was added followed by reflux for 1 h.The reaction mixture was made alkaline With aq. sodium hydroxide andextracted with dichloromethane. Drying of the organic phase overmagnesium sulfate and removal of the solvent in vacuo gave an orange oilwhich was applied to a silica gel column (eluent:ethylacetate/heptane/triethyl amine=70:28:2). The title compound, 13a,crystallized as the oxalate salt from acetone by addition of oxalicacid. Yield: 2.3 g, mp: 182°-84° C.

In a similar manner were also prepared:

1'-[4-(2,3-Dihydro-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 13b, mp: 161°-64° C.

1'-[4-(2,3-Dihydro-3-indolyl)-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine],oxalate, 13c, mp: 105°-7° C.

2,3-Dihydro-3-[4-(4-(2-methoxyphenyl)-1-piperidinyl)-1-butyl]indol,oxalate, 13d, mp: 160°-62° C.

EXAMPLE 14

1'-[2-[5-Chloro-1-(4-fluorophenyl)-3-indolyloxy]-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 14a.

To a solution of methyl5-chloro-1-(4-fluorophenyl)-3-indolone-2-carboxylate (50 g) andpotassium carbonate (40 g) in 500 ml of acetone, ethyl bromoacetate (35g) in 100 ml of acetone was added dropwise under reflux. After refluxfor 6 h the mixture was filtered and the solvent removed in vacuo.Addition of water and extraction with ether gave, after drying overmagnesium sulfate and removal of solvent in vacuo, a viscous oil, methyl5-chloro-3-ethoxycarbonylmethoxy-1-(4-fluorophenyl)indole-2-carboxylate,62 g. The oil was dissolved in 800 ml of ethanol and 30 g of potassiumhydroxide added. Reflux for 4 h, addition of 4 1 of crushed ice followedby acidification with hydrochloric acid gave a colorless solid which wasdissolved in 250 ml of NMP. Copper bronze (5 g) was added and themixture kept at 200° C. for 4 h. Addition of water and extraction withethyl acetate gave, after drying over magnesium sulfate and removal ofsolvent in vacuo, 27 g of 5-chloro-1-(4-fluorophenyl)-3-indolyloxyacetic acid. The acid was dissolved in 500 ml of tetrahydrofuran andlithium aluminium hydride (4 g) was added. After reflux for 3 h, thereaction mixture was hydrolyzed with water, filtered, and concentratedin vacuo giving 18 g of5-chloro-1-(4-fluorophenyl)-3-(2-hydroxyethyloxy)-indole as an oil. Theoil was dissolved in 250 ml of dichloromethane and triethyl amine (10ml) was added. Methanesulfonyl chloride (10 ml) was added dropwise at0°-5° C. followed by stirring for 4 h. The reaction mixture was washedwith water, dried over magnesium sulfate and concentrated in vacuo,leaving 5-chloro-1-(4-fluorophenyl)-3-indolyloxyethyl methanesulfonate(21 g) as a viscous oil.

1'-[2-[5-chloro-1-(4-fluorophenyl)-3-indolyloxy]-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine],14a, was prepared from 5-chloro-1-(4-fluorophenyl)-3-indolyloxyethylmethanesulfonate (3 g) and spiro[isobenzofuran-1(3H),4'-piperidine] bythe method described in EXAMPLE 2 followed by purification by columnchromatography (silica gel, eluent:ethyl acetate). The title compoundcrystallized as the oxalate salt from acetone. Yield: 0.8 g, mp:216°-17° C.

In a similar manner was also prepared:

5-Chloro-1-(4-fluorophenyl)-3-[2-(4-(4-fluorophenyl)-1-piperidinyl)-1-ethyloxy]indol,14b, mp: 102°-5° C.

EXAMPLE 15

1'-[3-(5-Fluorobenzofuran-3-yl)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 15.

The title compound was prepared from 3-(5-fluorobenzofuran-3-yl)propionic acid (3 g) and spiro[isobenzofuran-1(3H),4'-piperidine] (2 g)by the method described in EXAMPLE 12.3-(5-Fluoro-benzofuran-3-yl)-propionic acid was prepared by a proceduresimilar to the preparation of3-(2,3-dihydro-5-fluorobenzofuran-3-yl)-propionic acid as described inEXAMPLE 11, but omitting the reduction with magnesium turnings. Thetitle compound, 8, crystallized as the oxalate salt from acetone byaddition of oxalic acid. Yield: 2.6 g, mp: 157°-59° C.

EXAMPLE 16

1'-[4-(5-Fluorobenzofuran-3-yl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 16.

The title compound was prepared from 4-(5-fluorobenzofuran-3-yl) butyricacid (3.5 g) and spiro[isobenzofuran-1(3H),4'-piperidine] (3 g) by themethod described in EXAMPLE 12. 4-(5-Fluoro-benzofuran-3-yl) butyricacid was prepared by a procedure analogous to the preparation of4-(2,3-dihydro-5-fluoro-benzofuran-3-yl) butyric acid as described inEXAMPLE 12, applying 3-(5-fluorobenzofuran-3-yl)-1-propanol instead ofthe corresponding dihydro analogue.3-(5-Fluoro-benzofuran-3-yl)-1-propanol is prepared by the proceduredescribed in EXAMPLE 11, but omitting the reduction with magnesiumturnings. The title compound, 16, crystallized as the oxalate salt fromacetone by addition of oxalic acid. Yield: 4.8 g, mp: 154°-56° C.

EXAMPLE 17

1'-[4-[1-(4-Fluorophenyl)-5-trifluoromethylindazol-3-yl]-1-butyl]spiro]isobenzofuran-1(3H),4'-piperidine],17a.

To a suspension of magnesium turnings (135 g) in 300 ml of drytetrahydrofuran, ethyl bromide (140 g) dissolved in 500 ml of drytetrahydrofuran was slowly added followed by reflux for 20 min. Asolution of 4-chloro-1-butanol (274 g) in 500 ml of tetrahydrofuran wasadded dropwise at reflux temperature. After stirring for 20 min, theGrignard solution was filtered and added portionwise to a solution of2-chloro-4-trifluoromethyl-benzonitril (200 g) in 600 ml of drytetrahydrofuran. The reaction mixture was stirred for 16 h at roomtemperature followed by addition af 2N hydrochloric acid and ice.Extraction with ether, drying of the ether phase over magnesium sulfateand removal of solvent in vacuo left a viscous oil which was applied toa silica gel column (eluent:dichloromethane/ether=3:1) giving4-(2-chloro-5-trifluoromethylbenzoyl)-1-butanol (101 g) as an oil. Theoil (80 g) was dissolved in 800 ml of ethanol and hydrazine hydrate (160ml) was added followed by refluxing for 20 h. The reaction mixture wascooled and concentrated in vacuo. Water was added followed by extractionwith ether. Drying of the ether phase over magnesium sulfate and removalof solvent in vacuo gave 79 g of the hydrazone of4-(2-chloro-5-trifluoromethyl-benzoyl)-1-butanol as an oil. Thehydrazone (20 g) was dissolved in dimethyl formamide and potassiumtert-butoxide (10 g) was added. The mixture was kept at 100°-120° C. for30 min followed by addition of aq. ammonium chloride. Extraction withethyl acetate, drying of the ethyl acetate phase over magnesium sulfate,and removal of solvent in vacuo gave a viscous oil which was applied toa silica gel column (eluent:ethyl acetate) giving crystalline4-(5-trifluoromethyl-3-indazolyl)-1-butanol (2.7 g, mp: 177°-79° C.).The indazole (2.7 g) was arylated with 1-fluoro-4-iodobenzene (5 g) bythe method described in EXAMPLE 5 giving4-[1-(4-fluorophenyl)-5-trifluoromethyl-3-indazolyl]-1-butanol (2.7 g,mp: 77°-79° C.) which was converted to the correspondingmethanesulfonate by the method described in EXAMPLE 2. The titlecompound, 17a, was prepared from the methanesulfonate (2 g) andspiro[iso-benzofuran-1(3H),4'-piperidine] (2 g) by the method describedin EXAMPLE 2. Yield: 1.7 g, mp: 74°-76° C.

In a similar manner was also prepared:

4-Fluorophenyl-3-[4-(4-(4-fluorophenyl)-1-piperidinyl)-1-butyl]-5-trifluoromethylindazol,17b, mp: 124°-25° C.

EXAMPLE 18

1'-[4-(5-Trifluoromethylindazol-3-yl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],18.

4-(2-Chloro-5-trifluoromethylbenzoyl)-1-butanol, prepared as describedin EXAMPLE 17, was converted to the corresponding methanesulfonate bythe method described in EXAMPLE 2. Treatment withspiro[isobenzofuran-1(3H),4'-piperidine] according to the methoddescribed in EXAMPLE 2 gave1'-[4-(2-chloro-5-trifluoromethylbenzoyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine].Conversion to the corresponding hydrazone and ring closure according tothe method described in EXAMPLE 17 gave the title compound, 18, mp:146°-47° C.

EXAMPLE 19

1'-(4-(1,2-Benzisoxazol-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 19a, mp: 164°-65° C.

A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G.Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated withdry HCl (150 ml) and methanol (200 ml) was stirred for 2 h at roomtemperature. Removal of the volatiles in vacuo gave methyl1,2-benzisoxazole-3-acetate (17 g) as an oil. The oil was dissolved intetrahydrofuran (100 ml) and added dropwise to a suspension of lithiumaluminium hydride (6 g) in tetrahydrofuran (200 ml) at 0°-10° C.followed by stirring for 30 min at 15° C. Usual work-up gave2-(1,2-benzisoxazol-3-yl)ethanol (13 g) as an oil.

The ethanol derivative (13 g) was converted to the correspondingmethanesulfonate by the method described in EXAMPLE 2 (yield: 20 g). Asolution of the methanesulfonate (20 g) in dimethyl sulfoxide (20 ml)was added to a suspension of sodium cyanide (15 g) in dimethyl sulfoxide(40 ml) at 70° C. followed by stirring for 30 min at 70°-80° C. Waterand ether was added, the phases separated and the ether phase dried overmagnesium sulfate. Removal of solvent in vacuo gave3-(1,2-benzisoxazol-3-yl)propionitrile a solid (13 g, mp: 67° C.). Thenitrile was dissolved in methanol (200 ml) and HCl-saturated ether (200ml) is was added followed by stirring for 16 h at room temperature. Thereaction mixture was concentrated in vacuo, water and ether added, andthe phases separated. Drying of the ether phase over magnesium sulfateand removal of solvent in vacuo gave methyl3-(1,2-benzisoxazol-3-yl)propionate (13 g) as an oil. By repeating theabove mentioned steps the 3-(1,2-benzisoxazol-3-yl)propionate wasconverted to methyl 4-(1,2-benzisoxazol-3-yl)butyrate which was reducedwith lithium aluminium hydride according to the procedure describedabove to 4-(1,2-benzisoxazol-3-yl)-1-butanol. By the method described inEXAMPLE 2, 4-(1,2-benzisoxazol-3-yl)-1-butyl methanesulfonate wasobtained. The title compound 19a was obtained from4-(1,2-benzisoxazol-3-yl)-1-butyl methanesulfonate (3.4 g) andspiro[isobenzofuran-1(3H),4'-piperidine] (2 g) by the proceduredescribed in EXAMPLE 2. The oxalate salt crystallized from acetone byaddition of oxalic acid. Yield: 2.4 g, mp: 164°-65° C.

In a similar manner were also prepared:

3-[4-(4-(4-Fluorophenyl)-1-piperidyl)-1-butyl]-1,2-benzisoxazole,oxalate, 19b, mp: 174°-75° C.

1-(4-(1,2-Benzisoxazol-3-yl)-1-butyl)spiro[3H-2-benzopyran-3,4'-piperidine],oxalate, 19c, mp: 162°-63° C.

3-[4-(4-(2,6-Dichlorophenyl)-1-piperidyl)-1-butyl]-1,2-benzisoxazol,fumarate, 19d, mp: 196°-97° C.

EXAMPLE 20

1'-(3-(1,2-Benzisoxazol-3-yl)-1-propyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 20, mp: 131°-32° C.

The title compound 20 was prepared from3-(1,2-benzisoxazol-3-yl)-1-propanol (3.2 g, prepared as described inEXAMPLE 19 and spiro[isobenzofuran-1(3 H),4'-piperidine] (2 g) by themethod described in EXAMPLE 2. The product crystallized as the oxalatesalt from acetone by addition of oxalic acid. Yield: 2.3 g, mp: 131°-32°C.

EXAMPLE 21

3-[3-(4-(4-Fluorophenyl)-piperidin-1-yl)-1-propyloxy]-1,2-benzisothiazole,21.

A mixture of 4-(4-fluorophenyl)-piperidine (15 g), ethyl3-bromopropionate (20 g), and potassium carbonate (14 g) in methylisobutyl ketone was refluxed for 16 h. Filtration and removal of solventin vacuo gave 26 g of crude ethyl3-(4-(4-fluorophenyl)-1-piperidyl)propionate as an oil which was useddirectly in the next step. The oil was dissolved in dry tetrahydrofuran(70 ml) and added dropwise to a suspension of lithium aluminium hydride(6.5 g) in dry tetrahydrofuran (250 ml) at 15° C. under nitrogen gas.After stirring for 30 min at room temperature, water (6.5 ml), 10Nsodium hydroxide (7 ml), and water (30 ml) were added, subsequently.Filtration and removal of solvent gave 20 g of crude3-(4-(4-fluorophenyl)-1-piperidyl)-1-propanol as an oil which wassufficiently pure for use in the next step. A solution of3-(4-(4-fluorophenyl)-1-piperidyl)-1-propanol (10 g) in dry toluene (150ml) was treated portionwise with a 50% xylene suspension of sodiumhydride (3 g). A solution of 3-chloro-1,2-benzisothiazole (3.6 g) in drytoluene (30 ml) was added dropwise at room temperature followed bystirring for 1.5 h at room temperature. Ice was added, the phasesseparated and the aqueous phase extracted with ether.

Drying of the combined organic phases over magnesium sulfate and removalof solvents in vacuo gave an oil which was applied to columnchromatography (silica gel, eluent:ethyl acetate/heptane/triethylamine=50:50:4). The title compound 21 crystallized from a mixture ofisopropyl ether/heptane. Yield: 1.5 g, mp: 91°-92° C.

EXAMPLE 22

1'-(4-(1,2-Benzisothiazol-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 22.

4-(1,2-Benzisothiazol-3-yl)butyric acid (C. Branca et al, Phytochemistry14, 1975, 2545) (17 g) was dissolved in dry toluene (500 ml) and cooledto -10° C. Di-tertbutyl aluminium hydride (120 ml of an 1M solution intoluene) was added dropwise at -10° C. followed by stirring for 2 h atroom temperature. Dilute sulfuric acid (2M, 300 ml) was added, thephases separated, the aqueous phase extracted with ether, and thecombined organic phases dried over magnesium sulfate. Removal ofsolvents in vacuo left a viscous oil which was purified by columnchromatography (silica gel, eluent:ether).4-(1,2-Benzisothiazol-3-yl)-1-butanol (5.2 g) was obtained as an oil.

The title compound 22 was obtained from4-(1,2-benzisothiazol-3-yl)-1-butanol andspiro[isobenzofuran-1(3H),4'-piperidine] by the method described inEXAMPLE 2. The oxaIate salt crystallized from acetone by addition ofoxalic acid. Yield: 2 g, mp: 151°-52° C.

EXAMPLE 23

1-(4-Fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8-azabicyclo[3,2,1]-oct-2-en-8-yl]-1-butyl]-indol,23.

A mixture of dry ether (600 ml) and 15% BuLi in hexane (500 ml) wascooled to -45° C. A solution of 4-bromo-1-fluorobenzene (145 g) in dryether (350 ml) was added dropwise at -45° C. followed by stirring for 1h. A solution of 8-methyl-8-azabicyclo[3,2,1]octan-3-one (85 g) in dryether (400 ml) was added dropwise at -50° C. followed by stirring for 30min, the temperature raising to -20° C. The reaction mixture was pouredinto 2M hydrochloric acid and the phases separated. The ether phase wasextracted with 2M hydrochloric acid and the combined aqueous phases madealkaline with aqueous NaOH. Extraction with ethyl acetate, drying of theorganic phase over magnesium sulfate and removal of solvent in vacuo,gave 3-(4-fluorophenyl)-3-hydroxy-8-methyl-8-azabicyclo[3,2,1]octane (96g) as a solid, mp: 169° C.

The product was dissolved in trifluoroacetic acid (500 ml) followed byreflux for 1 h. The reaction mixture was concentrated in vacuo, wateradded and the mixture made alkaline with aqueous NaOH (pH>9). Extractionwith ethyl acetate, drying of the organic phase over magnesium sulfate,and removal of solvent in vacuo gave3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-ene as a solid (91g, mp: 62°-63° C. The product was dissolved in 1,1,1-trichloroethane(550 ml) and heated to 70° C. A solution of 2,2,2-trichloroethylchloroformate (14 ml) in 1,1,1-trichloroethane (25 ml) was addeddropwise at 70° C. followed by reflux for 1 h. Additional2,2,2-trichloroethyl chloroformate (24 ml) was added followed by refluxfor 5 h. Removal of volatiles in vacuo and purification by columnchromatography (silica gel, eluent:methylene chloride) gave3-(4-fluorophenyl)-8-(2,2,2-trichloroethyloxycarbonyl)-8-azabicyclo[3,2,1]oct-2-ene(59 g) as an oil.(4-Fluorophenyl)-8-(2,2,2-trichloroethyloxycarbonyl)-8-azabicyclo[3,2,1]oct-2-ene(17 g) was dissolved in glacial acetic acid (170 ml) followed byaddition of water (20 ml). The mixture was heated to 50° C. and zinkdust (40 g) was added in portions. After stirring for 2 h at 50° C. themixture was filtered and concentrated in vacuo. Water was added and themixture made alkaline with aqueous NaOH. Extraction with ethyl acetate,drying of the organic phase over magnesium sulfate and removal ofsolvent in vacuo left 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene (7g) as an oil. The title compound 23 was prepared from3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene according to the methoddescribed in EXAMPLE 9. Yield: 1.9 g, mp: 74°-75° C.

EXAMPLE 24

3-[4-[3-(4-Fluorophenyl)-8-azabicyclo[3.2.1]octan-8-yl]-1-butyl]-1,2-benzisoxazole,oxalate, 24, mp 169-170.

A solution of 3-(4-fluorophenyl)-8-azabicyclo[3,2,1]oct-2-ene (10 g) wasdissolved in glacial acetic acid (150 ml). Platinum oxide (0.5 g) wasadded followed by treatment with hydrogen gas at 3 atm of pressure in aconventional Parr apparatus. Filtration and removal of solvent in vacuoleft a viscous oil. Water was added and the mixture made alkaline (pH>9)with aqueous NaOH. Extraction with ethyl acetate, drying of the organicphase over magnesium sulfate and removal of solvent in vacuo gave3-(4-fluorophenyl)-8-azabicyclo[3,2,1]-octane (9 g) as an oil. The titlecompound 24 was obtained from3-(4-fluorophenyl)-8-azabicyclo[3,2,1]octane and4-(1,2-benzisoxazol-3-yl)-1-butyl methanesulfonate (prepared asdescribed in EXAMPLE 19) by the method described in EXAMPLE 2. Theoxalate salt crystallized from acetone by addition of oxalic acid.Yield. 1.1 g, mp: 169°-70° C.

EXAMPLE 25

1'-(4-Phenyl-1-butyl)-spiro[1,3-benzodioxole-2,4'-piperidine], maleate,25a.

A mixture of 1-ethoxycarbonyl-4-piperidinone (17 g), pyrocatechol (13 g)and p-toluenesulfonic acid (2.5 g) in 250 ml of dry toluene was refluxedwith continuous removal of water. After 3 h the reaction mixture wasconcentrated in vacuo, 2% NaOH (200 ml) was added followed by extractionwith dichloromethane. After drying over magnesium sulfate and removal ofsolvent in vacuo, the remaining red oil was applied to a silica gelcolumn (eluent:ethyl acetate/heptane=1:1) giving 22 g of a slightlyyellow oil, 1'-ethoxycarbonyl-spiro[1,3-benzodioxole-2,4'-piperidine].The oil was dissolved in ethanol (250 ml), NaOH (10 g) and water (20 ml)were added and the mixture refluxed for 20 h. Removal of the solvents invacuo addition of salt water followed by extraction with dichloromethanegave, after drying the organic phase over magnesium sulfate and removalof the solvent in vacuo, a red oil which was applied to a silica gelcolumn (eluent:ethyl acetate/methanol/triethylamine =4:5:1 ) yielding 10g of colorless crystals, spiro[1,3-benzodioxole-2,4'-piperidine], mp:108°-10° C. The title compound, 25a, prepared from 4-phenyl-1-butylmethanesulfonate (2.3 g) and spiro[1,3-benzodioxole-2,4'-piperidine](1.9 g) according to the method described in EXAMPLE 2, crystallized asthe maleate salt from acetone by addition of maleic acid. Yield: 1.6 g,mp: 156°-57° C.

In a similar manner was also prepared:

1'-[4-(3-Indolyl)-1-butyl]-spiro[1,3-benzodioxole-2,4'-piperidine], 25b,mp: 144°-49° C.

EXAMPLE 26

1'-[4-(4-Fluorophenyl)-4-hydroxy-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 26a.

1'-(3-(4-Fluorobenzoyl)-1-propyl)-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate (2 g), obtained from 1-chloro-3-(4-fluorobenzoyl)-propane andspiro[isobenzofuran-1(3H),4'-piperidine] by the method described inEXAMPLE 1, was dissolved in 100 ml of EtOH. Platinum oxide (0.1 g) wasadded and the mixture was hydrogenated in a Parr apparatus at 3 atm ofhydrogen pressure for 16 h. Filtration and concentration in vacuo gave,after addition of a mixture of ethyl acetate/acetone, crystalline 26a.Yield: 1.5 g, mp: 75°-80° C.

In a similar manner were also prepared:

1'-(4-Phenyl-4-hydroxy-1-butyl)-spiro[isobenzofuran-1(3H),4'-piperidine],26b, mp: 139°-40° C.

1'-(4-Cyclohexyl-4-hydroxy-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 26c, mp: 87°-89° C.

EXAMPLE 27

1'-(4-(1H-Inden-3-yl)-1-butyl)-spiro[isobenzofuran-1(3H),4'-piperidine],27.

A suspension of activated zinc (80 g) in dry tetrahydrofuran (200 ml)was heated to reflux and a few crystals of iodine was added. A solutionof 1-indanone (100 g) and methyl 4-bromo-crotonate (200 g) in 500 ml ofdry tetrahydrofuran was added dropwise followed by reflux for 1 h. Aftercooling, ice and aq. ammonium chloride was added followed by extractionwith dichloromethane. Removal of the solvent in vacuo gave a viscous oilwhich was purified on a silica gel column (eluent:dichloromethane/ether=1:1) giving methyl 4-(1-hydroxyindan-1-yl)-crotonate (78 g). A solutionof the crotonate (20 g) was dissolved in 200 ml dry ether and addeddropwise to a suspension of lithium aluminium hydride (10 g) in 150 mlof dry ether. After reflux for 1 h, the reaction mixture was hydrolyzedwith water. Filtration, drying of the ether phase over magnesiumsulfate, and removal of solvent in vacuo gave4-(1-hydroxyindan-1-yl)-1-butanol (18 g) as an oil. The alcohol (16 g)was dissolved in methanol (250 ml) and concentrated hydrochloric acid(40 ml) was added. After stirring for 30 min at room temperature, thereaction mixture was concentrated in vacuo, water was added and themixture extracted with ether. Drying of the ether phase over magnesiumsulfate and removal of solvent in vacuo gave a viscous oil which wasapplied to a silica gel column (eluent:dichloromethane/ether=9:1) giving4-((1H)inden-3-yl)-1-butanol (1.8 g). By the method described in EXAMPLE2, the alcohol was converted to the corresponding methanesulfonate andthe title compound, 27, was obtained usingspiro[isobenzofuran-1(3H),4'-pi-peridine], mp: 79°-80° C.

EXAMPLE 28

1'-[4-(Indan-1-yl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 28.

A suspension of activated zinc (40 g) in dry tetrahydrofuran (150 ml)was heated to reflux and a few crystals of iodine was added. A solutionof 1-indanone (50 g) and methyl 4-bromo-crotonate (100 g) in 400 ml ofdry tetrahydrofuran was added dropwise followed by reflux for 1 h. Aftercooling, ice was added and the pH adjusted to 1 with concentratedhydrochloric acid followed by extraction with dichloromethane.Concentration of the organic phase left a viscous oil which wasdissolved in methanol (400 ml). Concentrated hydrochloric acid (100 ml)was added and the mixture stirred for 30 min. Removal of solvents invacuo, addition of water, and extraction with ether gave, after dryingover magnesium sulfate and removal of solvent in vacuo, an oil (34 g).The oil was dissolved in 300 ml of dry ether and added dropwise to asuspension of lithium aluminium hydride (21 g). After reflux for 2 h,the reaction mixture was hydrolyzed with water. Filtration and removalof solvent in vacuo gave a mixture of isomers from which4-(1-indanyl)-but-3-en-1-ol (6 g) could be isolated by columnchromatography (silica gel, eluent:dichloromethane/ether =9:1). Theremaining mixture of isomers (9 g) was dissolved in 150 ml of methanoland hydrogenated at 3 atm of hydrogen pressure in is a conventional Parrapparatus in the presence of 5% palladium on charcoal (6 g) for 12 h.Filtration and removal of solvent in vacuo gave 6 g of4-(1-indanyl)-1-butanol. The alcohol was converted to the titlecompound, 28, via the corresponding methanesulfonate following theprocedures described in EXAMPLE 2 usingspiro[isobenzofuran-1(3H),4'-piperidine], mp: 114°-15° C.

EXAMPLE 29

1'-[4-(1-Indanyl)-but-3-en-1-yl]-spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 29.

4-(1-Indanyl)-but-3-en-1-ol, prepared as described in EXAMPLE 28, wasconverted to the corresponding methanesulfonate by the method describedin EXAMPLE 2. The title compound was prepared by the method described inEXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine], mp: 108°-9° C.

EXAMPLE 30

1'-(4-(2,3-Dihydro-1-(4-fluorophenyl)-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 30.

To a solution of 5a (2 g) in trifluoroacetic acid (30'ml), sodiumcyanborohydride (0.5 g) in methanol (25 ml) was added dropwise. Afterstirring for 2 h at room temperature the mixture was concentrated invacuo, ethyl acetate (50 ml) was added followed by washing with 2Nsodium hydroxide (2×50 ml). Drying of the organic phase over sodiumsulfate and removal of solvent in vacuo gave the title base whichcrystallized as the oxalate salt from acetone by addition of oxalicacid. Yield: 0.7 g, mp: 172°-73° C.

EXAMPLE 31

1'-[3-(Benzo[b]thiophen-3-ylthio)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],maleate,31a.

A solution of benzo[b]thiophen-3-one (20 g), 3-mercaptopropionic acid(25 ml), 2N hydrochloric acid (3 ml) in xylene (80 ml) was refluxed for18 h. Water (100 ml) and ether (300 ml) were added and the phasesseparated. The ether phase was extracted with 150 ml 2N NaOH followed byacidification of the alkaline phase with conc. hydrochloric acid.Extraction with ether, drying of the ether phase over magnesium sulfateand removal of solvent gave 15.6 g of a viscous oil,3-(benzo[b]thiophen-3-ylthio)-propionic acid. The acid was dissolved in100 ml of tetrahydrofuran and added dropwise to a suspension of lithiumaluminium hydride (4 g) in tetrahydrofuran (150 ml). After reflux for 3h, the reaction was quenched with water followed by usual work-up giving12.7 g of 3-(benzo[b]thiophen-3-ylthio)-1-propanol as an oil. The titlecompound 31 a was obtained by the method described in EXAMPLE 2 usingspiro[isobenzofuran-1(3H),4'-piperidine] and crystallized as the maleatefrom acetone by addition of maleic acid. Yield: 0.9 g, mp: 154°-55° C.

In a similar manner was also prepared:

1'-[3-(Benzo[b]thiophen-3-ylthio)-1-propyl]spiro[3H-2-benzopyran-3,4'-piperidine], maleate, 31b, mp:169°-70° C.

EXAMPLE 32

1'-[4-(2,3-Dihydro-benzo[b]thiophen-3-yliden)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine]-S,S-dioxide,maleate, 32.

A solution of 4-(3-benzo[b]thiophen-3-yl)-1-butyl methanesulfonate (4.4g), prepared as described in EXAMPLES 10 and 2, in glacial acetic acid(12 ml) was treated dropwise with aqueous 30 % hydrogen peroxide at roomtemperature followed by heating to 80° C. for 20 min. Upon cooling theproduct, 4-(3-benzo[b]thiophen-S,S-dioxide-3-yl)-1-butylmethanesulfonate, crystallized. Yield: 3.7 g, mp: 100°-1° C. Themethanesulfonate (1.4 g) was treated withspiro[isobenzofuran-1(3H),4'-piperidine]. HCl (1.2 g) according to themethod described in EXAMPLE 2 giving the title compound 32 whichcrystallized as the maleate from acetone by addition of maleic acid.Yield: 1 g, mp: 186°-87° C.

EXAMPLE 33

1'-[4-(2,3-Dihydro-benzo[b]thiophen-3-yl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine]-S,S-dioxide,maleate, 33.

Oxidation of 4-(benzo[b]thiophen-3-yl)butyric acid (8.5 g) according tothe method described in EXAMPLE 32 gave the corresponding S,S-dioxide(9.2 g). A solution of the acid (4 g) in tetrahydrofuran (25 ml) wasadded dropwise to a suspension of lithium aluminium hydride (1.3 g) intetrahydrofuran (50 ml) at 0° C. followed by stirring at roomtemperature for 2 h. Usual work-up yielded 3 g of4-(2,3-dihydro-benzo[b]thiophen-S,S-dioxide-3-yl)-1-butanol which wasconverted to the title compound by treatment withspiro[isobenzofuran-1(3H),4'-piperidine] according to the methoddescribed in EXAMPLE 2. The product crystallized as the fumarate from anacetone/ethanol mixture upon addition of fumaric acid. Yield: 1.5 g, mp:197°-98° C.

EXAMPLE 34

1'-[3-(Benzo[b]thiophen-3-yloxy)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine],maleate, 34.

A mixture of benzo[b]thiophen-3-one (30 g), ethyl 3-bromopropionate (73g), potassium carbonate (55 g), potassium iodide (1.3 g) and acetone(600 ml) was refluxed for 18 h. Filtration and removal of solvent invacuo a red oil which was dissolved in ether (200 ml) and dried overmagnesium sulfate. The ether solution was added dropwise to a suspensionof lithium aluminium hydride (5 g) in ether (100ml) followed by refluxfor 1 h. Usual work-up gave a viscous oil which was applied to a silicagel Column (eluent:isopropyl ether) giving3-(benzo[b]thiophen-3-yloxy)-1-propanol (0.54 g) as an oil. The titlecompound was obtained according to the method described in EXAMPLE 2using spiro[isobenzofuran-1(3H),4'-piperidine] and crystallized as themaleate salt from an acetone/ether mixture by addition of maleic acid.Yield: 0.34 g, mp: 116°-17° C.

EXAMPLE 35

1'-[2-(Benzo[b]thiophen-3-ylmethyloxy)-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine],fumarate, 35a.

An ether solution (50 ml) of methyl benzo[b]thiophene-3-carboxylate (15g) was added dropwise to a suspension of lithium aluminium hydride (3.5g) in ether (100 ml) followed by reflux for 2 h. Usual work-up gavebenzo[b]thiophen-3-yl methanol (13.5 g) as an oil. The oil was dissolvedin tetrahydrofuran (50 ml) and added dropwise to a suspension of NaH (5g of an 80% paraffinsuspension) in tetrahydrofuran (100 ml) followed byreflux for 1 h. Ethyl bromoacetate (35 g) in tetrahydrofuran (50 ml) wasadded at 60° C. followed by reflux for 1 h. Additional ethylbromoacetate (20 g) was added followed by reflux for 7 h. The reactionwas quenched with water and the volatiles removed in vacuo. Theremaining oil was applied to a silica gel column (eluent:ethylacetate/heptane 2:8) giving ethyl benzo[b]thiophen-3-ylmethyloxyacetate(5 g) as an oil. Reduction with lithium aluminium hydride as describedabove yielded 3.8 g of 2-(benzo[b]thiophen-3-ylmethyloxy)ethanol as anoil. The title compound 35a was obtained by the method described inEXAMPLE 2 using spiro[isobenzofuran-1(3H),4'-piperidine] andcrystallized as the fumarate salt from an acetone/ethanol mixture byaddition of fumaric acid. Yield: 0.55 g, mp: 149°-50° C.

In a similar manner was also prepared:

1'-[2-(5-Fluorobenzofuran-3-ylmethyloxy)-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 35b, mp: 148°-49° C.

1'-[2-(Benzofuran-3-ylmethyloxy)-1-ethyl]-4-fluorospiro[isobenzofuran-1(3H),4'-piperidine],oxalate, 35c, mp: 120°-22° C.

EXAMPLE 36

1'-[4-(1-(2-Dimethylamino-1-ethyl)-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine],dihydrochloride, 36.

A solution of 4-(3-indolyl)-1-butanol (5 g) in dry DMF (50 ml) wascooled to 10° C. followed by treatment with potassium t-butoxide (3 g).After stirring for 5 min. 2-chloro-N,N-dimethylacetamide (3.5 g)dissolved in dry DMF (10 ml) was added dropwise at 10°-15° C. Afterstirring for 1 h at room temperature water was added followed byextraction with ethyl acetate. Drying of the organic phase overmagnesium sulfate and removal of solvent in vacuo left a viscous oil,4-(1-dimethylaminocarbonylmethyl-3-indolyl)-1-butanol (7 g) which wasconverted to1'-[4-(1-dimethylaminocarbonylmethyl-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine]by the method described in EXAMPLE 2 usingspiro[isobenzofuran-1(3H),4'-piperidine]. Yield: 5.7 g of a viscous oil.Conventional reduction with lithium aluminium hydride gave the titlecompound 36 which crystallized as the dihydrochloride from acetone byaddition of hydrochloric acid. Yield: 2.4 g, mp: 244°-45° C.

PHARMACOLOGY

Some of the compounds of Formula I have been tested according to anestablished and reliable pharmacological test as follows:

INHIBITION OF ³ H-DTG BINDING TO SIGMA RECEPTORS IN RAT BRAIN IN VITRO.

By this method the inhibition by drugs of the binding of 2 nM ³ H-DTG(1,3,di-o-tolyl guanidine) to sigma receptors in homogenates ormembranes from rat brain without cerebellum is determined in vitro asmodified from Weber et al. Proc. Natl. Acad. Sci. 1986, 83, 8784.

Tissue preparations:

Homogenate: Rats (15-250 g) are decapitated and the brains (withoutcerebellum) quickly removed and placed on ice, weighed and homogenizedin 100 vol ice-cold (0° C.) 50 mM Tris-buffer (pH 7.7) in an ethanolrinsed glass/teflon homogenizer at 0° C. and kept on ice until use.

P2-membranes: Brains are homogenized in 10 vol 0.32M sucrose in anethanol rinsed glass/teflon homogenizer with 10 strokes up and down. Thehomogenate is centrifuged for 10 min at 900× g_(m) at 4° C. Thesupernatant is decanted and centrifuged for 20 min at 50,000 g_(m) at 4°C. The resulting pellet is resuspended in 10 vol ice-cold 50 nMTris-buffer (pH 7.7) and incubated for 30 min. at 37° C. The membranesuspension is then centrifuged for further 20 min. at 50,000 g_(m) at 4°C. The pellet is resuspended in 50 vol. of ice-cold Tris-buffer and usedimmediately.

Binding analysis:

0.5 ml 50 mM Tris-buffer (pH 7.7), 0.25 ml displacer (6×100 μM DTG,6×[test compound], or Tris-buffer), and 0.25 ml 6×2 nM ³ H-DTG are mixedinto 5 ml plastic test tubes and kept at 4° C. until use. The bindingreaction is initiated by mixing 0.5 ml tissue suspension into thissolution and incubate at 25° C. for 20 min. Glass fiber filters (WhatmanGF/B) are placed on the filter machine which is then closed tightly.Just before filtration vacuum is applied, and the filters washed with0.1% PEI solution from a spray bottle followed by one wash withTris-buffer. The binding reaction is stopped by filtration of the assaymixture at reduced pressure (750 mbar) followed by further 3 washes with5 ml ice-cold Tris-buffer. The filters are then placed in counting vialsand 4 ml scintillation solution added. The vials are counted in aBeckmann scintillation counter.

Buffers and solutions:

50 mM Tris-buffer pH 7.7:7.38 g Trizma-7.7 plus distilled H₂ O ad 1liter. 100 ml 10% polyethylenimine (PEI): 100 ml dest. H₂ O is added toapprox. 20 g 50% PEI which is solubilized by stirring and heating.Diluted (1+99) before use. 6×2 nM ³ H-DTG: The exact volume depends onthe actual concentration of the batch, but is made as close as possibleto 12 nM. The containers for the radioactive solution is rinsed in 96%ethanol before use. 6×100 μM DTG: 14.36 mg/100 ml is kept frozen in 10ml aliqouts. ³ H-DTG was obtained from NEN Research Products, Du PontDenmark. Specific activity 62.3 Ci/mmol.

The known sigma receptor ligands BMY 14802 and rimcazole were includedin the test for comparison purposes.

                  TABLE 1                                                         ______________________________________                                        .sup.3 H DTG Binding Data                                                                                               IC50                                Compound                                                                              IC50 (nM)                                                                              Compound  IC50 (nM)                                                                            Compound                                                                              (nM)                                ______________________________________                                        1a      7.3      4c        2.9    11a     0.31                                1b      3.7      4d        1.1    11b     0.63                                2a      0.25     4e        0.20   12      0.30                                2b      0.07     4f        0.20   13a     3.7                                 2c      0.51     4g        46     13b     1.0                                 2d      0.77     5a        0.33   13c     4.8                                 2e      1.2      5b        1.1    13d     2.1                                 2f      0.95     5c        0.25   14a     24                                  2g      0.36     5d        0.24   14b     3.8                                 2h      1.4      5e        4.7    15      0.42                                2i      4.3      5f        0.04   16      0.15                                2j      0.07     5g        4.0    17a     0.11                                2k      0.19     6a        0.05   17b     0.46                                21      3.8      6b        0.17   18a     0.56                                2m      0.47     6c        <0.1   19a     0.08                                2n      6.0      7         0.21   19b     0.49                                2o      0.26     8a        0.21   19c     0.84                                2p      0.32     8b        1.7    19d     4.4                                 2q      430      8c        0.66   20      0.63                                2r      3.0      8d        11     21      0.2                                 2s      3.1      9a        0.34   22      0.05                                2t      5.4      9b        0.06   23      2.5                                 2u      0.41     9c        0.14   24      1.9                                 2v      1.8      9d        26     25a     11                                  2x      1.6      9e        0.31   25b     36                                  2y      0.84     9f        27     26a     0.89                                2z      1.5      9g        4.2    26b     1.9                                 2aa     0.3      9h        2.3    26c     0.14                                2bb     0.30     9i        0.62   27      0.11                                2cc     1.1      9j        0.11   28      0.15                                2dd     1.7      9k        0.92   29      0.12                                2ee     1.0      9l        0.14   30      0.07                                2ff     0.43     9m        1.6    31a     0.23                                2gg     3.3      9n        6.3    31b     2.6                                 2hh     0.02     9o        6.7    32      0.89                                2ii     5.8      9p        0.28   33      0.95                                2jj     1.4      9q        0.12   34      0.27                                3a      2.2      9r        0.42   35a     0.73                                3b      4.8      9s        56     35b     2.8                                 3c      1.0      9t        3.2    36      4.5                                 3d      7.3      10a       0.09                                               4a      23       10b       1.3    BMY 14802                                                                             230                                 4b      0.53     10c       0.35   rimcazole                                                                             180                                 ______________________________________                                    

It is seen from Table I that the compounds used in the present inventionare very potent sigma receptor ligands as compared to the referencecompounds which are known in the art to be sigma receptor ligands, thepotencies for the compounds tested being better than about 40 nM, andfor most of the compounds tested better than about 1 nm.

Furthermore, the ability of the present compounds in inhibiting thebinding of ³ H-Prazosin to α₁ adrenoceptors in membranes from rat brainwere determined in vitro according to Hyttel, J et al, J. Neurochem,1985, 44, 1615; Skarsfeldt, T. et al, Eur. J. Pharmacol. 1986, 125, 323.

Additionally the compounds of the invention were tested respect todopamine D₂ receptor binding activity according to van der Welde et al,Eur. J. Pharmacol. 1987, 134, 211.

For most compounds, the affinities for α₁ adrenoceptors and D₂ receptorswere weak as compared to the potent binding to sigma receptors. Thusmany of the compounds are very selective sigma receptor ligands, havingratios of binding affinities (IC₅₀ alpha/IC₅₀ sigma and IC₅₀dopamine/IC₅₀ sigma, respectively) of 30-10000.

LIGHT/DARK DISCRIMINATION TEST IN RATS.

The test was carried out in accordance with F. C. Colpaert et al.,Psychopharmacology (1985) 86: 45-54. The test used Wistar WU rats.

The test was conducted using a two compartment activity box in which theactions of anxiolytic compounds to reduce aversion against abrightly-lit environment may be readily detected. The box is designed asan open-top experimental box one third of which was partitioned from therest, painted black and illuminated with red light. The remainder of thebox was painted white and brightly illuminated. The floor of each areawas lined into squares. Behavioural changes were recorded. Data obtainedfrom dose groups were analysed using single factor analysis of variance,and Dunnett's t-test. Test compounds were given intraperitoneally 45 minbefore testing. Several compounds have been tested in this test modeland showed significant anxiolytic activities with ED₅₀ values in theng-μg/kg dose range.

FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art. For example: Tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvants or additives usually used for such purposessuch as colourings, flavorings, preservatives etc. may be used providedthat they are compatible. with the active ingredients. Solutions forinjections may be prepared by dissolving the active ingredient andpossible additives in a part of the solvent for injection, preferablysterile water, adjusting the solution to desired volume, sterilizationof the solution and filling in suitable ampules or vials. Any suitableadditive conventionally used in the art may be added, such as tonicityagents, preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are asfollows:

1) Tablets containing 0.5 milligrams of Compound 3c calculated as thefree base:

    ______________________________________                                        Comp. 3c         0.5         mg                                               Lactose          18          mg                                               Potato starch    27          mg                                               Sucrose          58          mg                                               Sorbitol         3           mg                                               Talcum           5           mg                                               Gelatine         2           mg                                               Povidone         1           mg                                               Magnesium stearate                                                                             0.5         mg                                               ______________________________________                                    

2) Tablets containing 5 milligrams of Compound 2m calculated as the freebase:

    ______________________________________                                        Comp. 2m         5           mg                                               Lactose          16          mg                                               Potato starch    45          mg                                               Sucrose          106         mg                                               Sorbitol         6           mg                                               Talcum           9           mg                                               Gelatine         4           mg                                               Povidone         3           mg                                               Magnesium stearate                                                                             0.6         mg                                               ______________________________________                                    

3) Syrup containing per milliliter:

    ______________________________________                                        Comp. 6b       2.5           mg                                               Sorbitol       500           mg                                               Tragacanth     7             mg                                               Glycerol       50            mg                                               Methyl-paraben 1             mg                                               Propyl-paraben 0.1           mg                                               Ethanol        0.005         ml                                               Water          ad 1          ml                                               ______________________________________                                    

4) Solution for injection containing per milliliter:

    ______________________________________                                               Comp. 17a                                                                             1            mg                                                       Acetic acid                                                                           17.9         mg                                                       Sterile water                                                                         ad 1         ml                                                ______________________________________                                    

5) Solution for injection containing per milliliter:

    ______________________________________                                        Comp. 17b        0.1         mg                                               Sorbitol         42.9        mg                                               Acetic acid      0.63        mg                                               Sodium hydroxide 22          mg                                               Sterile water    ad 1        ml                                               ______________________________________                                    

We claim:
 1. A piperidine compound having Formula I: ##STR21## whereinR¹ is a group having the general Formula II: ##STR22## wherein X isCHR¹⁰, O, S, SO, SO₂ or NR¹⁰ ; wherein R¹⁰ is hydrogen, lower alkyl,lower alkenyl, sulfonyl, arylalkyl, phenyl or phenyl substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, lower alkoxy, hydroxy,trifluoromethyl, and cyano; orR¹⁰ is a heteroaromatic group, selectedfrom the group consisting of 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl,2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, and4-pyridyl; wherein one or two of the dotted lines may be a bond; whenthe dotted line emanating from Y indicates a bond, Y is N or CH; or whensaid dotted line indicates no bond, Y is CH₂, or NH; R^(a) -R^(d) areindependently selected from the group consisting of hydrogen, halogen,lower alkyl, trifluoromethyl and trifluoromethylthio; U is CH₂, O or S;or when, one of the dotted lines emanating from U indicates a bond and Uis CH; the bond between U and Q¹ or Q², respectively, may also be atriple bond and in such a case U is "C"; Q¹ is selected from a bond, C₁-C₁₈ alkylene or C₂ -C₁₈ alkenylene and Q² is C₂ -C₂₀ alkylene, C₂ -C₂₀alkenylene or a group Q² 'D wherein Q² ' is as defined for Q² and D isCR⁸ R⁹ wherein R⁸ and R⁹ are independently selected from thesubstituents defined below for R⁴ -R⁷, and a cycloalkylene group;wherein Q¹ and Q² are optionally substituted with one or more hydroxygroups, any such hydroxy group being optionally esterified with analiphatic carboxylic acid having from two to twenty-four carbon atoms,inclusive; wherein the total number of carbon atoms in Q¹ and Q² is from3 to 20; and R² and R³ are independently hydrogen, lower alkyl or theymay be linked together thereby forming an ethylene or propylene bridge;R⁴ to R⁷ are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl andtrifluoromethylthio; andZ¹ is CH₂, or O or S; Z² and Z³ areindependently (CH₂)_(n), wherein n is 0 or 1, O or S, with the provisothat Z¹ may not be S or O when Z² is S or O, and that Z² and Z³ may notboth be (CH₂), wherein n is 0: or Z¹ and Z² taken together represent agroup --CH═CH--; or when Z³ is (CH₂)_(n) wherein n is 0, Z¹ and Z² takentogether can form a 3-membered divalent group, optionally containing oneunsaturated bond, and optionally containing one O- or S-heteroatom; withthe proviso that the combination of Z¹, Z², and Z³ cannot represent abenzofuranyl system; and with the proviso that at least one of Z¹, Z²and Z³ is O or S; or an acid addition salt thereof.
 2. A compoundaccording to claim 1, wherein at least one of Z¹, Z² and Z³ designates Oor S.
 3. A compound according to claim 2, wherein Z³ is (CH₂)_(n)wherein n is 0, and Z² is "O" or "S" and Z¹ is CH₂ or Z¹ and Z² togetherrepresent CH₂ --O--CH₂.
 4. A compound to claim 2, wherein Z¹ is CH₂, Z²is O and Z³ is CH₂ ; or Z³ is O and Z¹ -Z² is CH═CH; or Z¹ is O, Z³ is Oand Z² is (CH₂)_(n) where n=0.
 5. A compound according to claim 1,wherein, the compound is selected from the group consistingof:1'-[4-(1-benzyl-3-indolyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine];1'-[4[1-(4-fluorophenyl)-3-indolyl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine];1,4-Dihydro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[3H-2-benzopyran-3,4'-piperidine];1'-(4-(1-p-toluenesulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];1'-[4-[5-fluoro-1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];6-fluoro-1'-[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];1'-[4-[1-(4-methylphenyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine];1'-[4-(1-(2-thiazolyl)-3-indolyl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];1'-[3-(5-flurobenzofuran-3-yl)-1-propyl]spiro[isobenzofuran-1(3H),4'-piperidine];'-[4-(5-fluorobenzofuran-3-yl)-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];1'-[4-[1-(4-fluorophenyl)-5-trifluoromethylindazol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine];1'-(4-(1,2-benzisoxazol-3-yl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];1'-[3-(benzo[b]thiophen-3-ylthio)-1-propyl]spiro[isobenzofuran-1(3H),4'piperidine];1'-(4-(1-methanesulfonyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];1'-(4(1-acetyl-3-indolyl)-1-butyl)spiro[isobenzofuran-1(3H),4'-piperidine];and1'[4-[1-(4-fluorophenyl)-3-indolyl]-1-butyl]spiro[1H-2-benzopyran-4(3H),4'-piperidine.6. A pharmaceutical composition, wherein said composition comprises from0.01 to about 50 mg of at least one piperidine compound according toclaim 1 or a pharmaceutically acceptable acid addition salt incombination with one or more pharmaceutically acceptable carriers ordiluents.
 7. A pharmaceutical composition, according to claim 6, fortreatment of anxiety, psychosis, epilepsy, convulsion, movementdisorders, motor disturbances, amnesia, cerebrovescular diseases, seniledementia of the Alzheimer type or Parkinson's disease.